Detection of reduced-control cardiac zones

ABSTRACT

A method of treating cardiac arrhythmia in a heart, including (i) determining that cardiac tissue is viable but with reduced innervation; and (ii) ablating the tissue to reduce a prevalence of arrhythmia in said heart. Optionally, the determining comprises detecting portions of heart wall which lack electrical activity. Optionally, at least some tissue which is viable but lacks nervous control is ablated, for example, to reduce or avoid arrhythmia.

RELATED APPLICATIONS

This application is a National Phase PCT Patent Application No.PCT/IB2014/064316 having International filing date of Sep. 8, 2014,which claims the benefit of priority under 35 USC § 119(e) of:

U.S. Provisional Patent Application No. 61/875,069 filed Sep. 8, 2013,U.S. Provisional Patent Application No. 61/875,070 filed Sep. 8, 2013,U.S. Provisional Patent Application No. 61/875,074 filed Sep. 8, 2013,U.S. Provisional Patent Application No. 61/925,670 filed Jan. 10, 2014,U.S. Provisional Patent Application No. 61/925,669 filed Jan. 10, 2014,U.S. Provisional Patent Application No. 62/003,108 filed May 27, 2014,U.S. Provisional Patent Application No. 62/030,740 filed Jul. 30, 2014,U.S. Provisional Patent Application No. 62/030,972 filed Jul. 30, 2014,and U.S. Provisional Patent Application No. 62/030,917 filed Jul. 30,2014.

PCT Patent Application No. PCT/IB2014/064316 is also aContinuation-in-Part (CIP) of PCT Patent Application No.PCT/IL2014/050086 filed Jan. 24, 2014, PCT Patent Application No.PCT/IL2014/050088 filed Jan. 24, 2014, PCT Patent Application No.PCT/IL2014/050089 filed Jan. 24, 2014, PCT Patent Application No.PCT/IL2014/050090 filed Jan. 24, 2014, and PCT Patent Application No.PCT/IL2014/050246 filed Mar. 11, 2014.

The contents of the above applications are incorporated by reference asif fully set forth herein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to detectionof tissue with reduced and/or mismatched innervation, and moreparticularly, but not exclusively, to detecting viable cardiac tissuethat lacks nervous control.

SUMMARY OF THE INVENTION

There is provided in accordance with an exemplary embodiment of theinvention, a method of treating cardiac arrhythmia in a heart,comprising: (i) determining that cardiac tissue is viable but withreduced innervation; and (ii) ablating the tissue to reduce a prevalenceof arrhythmia in said heart.

Optionally, said determining comprises detecting portions of heart wallwhich lack electrical activity. Optionally or alternatively, determiningcomprises determining a zone having a minimal dimension smaller than 20mm Optionally or alternatively, determining comprises determining a zonehaving a length of at least 50 mm Optionally or alternatively, ablatingcomprises ablating near regions of a heart wall where muscle died.Optionally or alternatively, ablating comprises ablating a boundaryregion between tissue with normal and tissue with reduced innervation.Optionally or alternatively, ablating comprises ablating less than 50%of tissue determined to have reduced innervation while being viable.Optionally or alternatively, the method comprises aligning saiddetermined reduced innervation tissue with electrophysiological data.Optionally or alternatively, the method comprises correlating saiddetermined reduced innervation tissue with one or both of theidentification of arrhythmic foci and identification of reentrant loop,and ablating based on a result of said correlating. Optionally oralternatively, the method comprises generating an image of a portion ofsaid heart delineating said tissue that is viable and with reducedinnervation. Optionally, said image has a resolution of better than 5 mmOptionally or alternatively, said image has at least three levels ofinnervation shown. Optionally or alternatively, generating the imagecomprises using dual isotope radioimaging. Optionally, said radioimagingcomprises using a model of the wall of the heart to reconstructemissions collected form said isotopes. Optionally or alternatively,said dual isotope imaging comprises reconstructing an image of viabilityusing one tracer and reconstructing an image of nervous control using asecond tracer and determining a mismatch between the two images.Optionally or alternatively, said dual isotopes comprise Tc-99 and I-131or I-123.

In an exemplary embodiment of the invention, generating an imagecomprises comparing an image indicating viability or tissue type with animage indication of nervous control.

In an exemplary embodiment of the invention, the method comprisesdisplaying said image to a physician.

In an exemplary embodiment of the invention, said determining comprisesdetermining using electrophysiological measurements.

There is provided in accordance with an exemplary embodiment of theinvention a method of cardiac mapping comprising: (i) identifyingportions of the heart with reduced nervous control; and (ii) arrangingsaid portions in a map.

Optionally, the method comprises identifying portions of the heart thatare viable and portions of the heart that are not viable. Optionally oralternatively, the method comprises identifying portions of the heartmuscle which are hibernating, with at least some electrical activity butno mechanical activity. Optionally or alternatively, the methodcomprises identifying portions of said heart with reduced ganglioncontrol. Optionally or alternatively, the method comprises diagnosing aheart ailment based on said map. Optionally, said diagnosing comprisesidentifying portion of said heart at risk for causing or maintainingarrhythmia.

In an exemplary embodiment of the invention, the method comprisestreating said heart based on said map. Optionally, said treatingcomprises ablating at least part of said identified portions withreduced nervous control. Optionally or alternatively, said treatingcomprises selecting a pharmaceutical regimen based on said map.Optionally or alternatively, said treating comprises selecting a pacinglocation or a pacing type based on said map. Optionally oralternatively, identifying comprises dual isotope radio imaging.

There is provided in accordance with an exemplary embodiment of theinvention a map showing portions of a heart wall that are mechanicallyactive but have reduced nervous control, stored on a non-volatilecomputer storage media.

There is provided in accordance with an exemplary embodiment of theinvention apparatus for carrying out the method described herein.

There is provided in accordance with an exemplary embodiment of theinvention apparatus comprising circuitry configured to compare aviability image with a nervous control image and generate a map ofportions with viability and reduced nervous control.

There is provided in accordance with an exemplary embodiment of theinvention a method of detecting or diagnosing a pathology due tounbalanced damage and/or functioning of body tissue, comprising: (i)measuring the distribution of functionality of a first affectedfunction; (ii) measuring the distribution of functionality of a secondaffected function; and (iii) identifying areas of unbalanced damage.

Optionally, said measuring comprises measuring using a nuclear medicineimager to detect differences in functionality within regions smallerthan 900×900×900 mm in volume, smaller than 600×600×600 mm in volume,smaller than 300×300×300 mm in volume, smaller than 70×70×70 mm involume, smaller than 50×50×50 mm in volume, smaller than 20×20×20 mm involume, smaller than 10×10×10 mm in volume, and/or intermediate orlarger volumes. Optionally, the volume of the functional region itselfis smaller than 70×70×70 mm in volume, smaller than 50×50×50 mm involume, smaller than 20×20×20 mm in volume, smaller than 10×10×10 mm involume, and/or intermediate or larger volumes.

According to an aspect of some embodiments of the present invention,there is provided a method of treating organ dysfunction due toautonomic innervation mismatch, comprising: (i) determining that tissueof an organ is viable but with reduced innervation; and (ii) ablatingbody tissue to reduce a prevalence of the dysfunction in the organ.

According to some embodiments of the invention, determining comprisesdetermining a zone having a minimal dimension smaller than 20 mm.

According to some embodiments of the present invention, there isprovided a method wherein determining comprises determining a zonehaving a length of at least 50 mm.

According to some embodiments of the present invention, there isprovided a method wherein ablating comprises ablating a boundary regionbetween tissue with normal and tissue with reduced innervation.

According to some embodiments of the present invention, there isprovided a method wherein ablating comprises ablating less than 50% oftissue determined to have reduced innervation while being viable.

According to some embodiments of the present invention, there isprovided a method comprising aligning the determined reduced innervationtissue with electrophysiological data.

According to some embodiments of the present invention, there isprovided a method comprising generating an image of a portion of theorgan delineating the tissue that is viable and with reducedinnervation.

According to some embodiments of the invention, the image has aresolution of better than 5 mm.

According to some embodiments of the invention, the image has at leastthree levels of innervation shown.

According to some embodiments of the invention, generating the imagecomprises using dual isotope radioimaging.

According to some embodiments of the invention, the radioimagingcomprises using a model of the anatomy of the organ to reconstructemissions collected from the isotopes.

According to some embodiments of the invention, the dual isotope imagingcomprises reconstructing an image of viability using one tracer andreconstructing an image of nervous control using a second tracer anddetermining a mismatch between the two images.

According to some embodiments of the invention, the dual isotopescomprise Tc-99 and I-131 or I-123.

According to some embodiments of the invention, generating an imagecomprises comparing an image indicating viability or tissue type with animage indication of nervous control.

According to some embodiments of the present invention, there isprovided a method comprising displaying the image to a physician.

According to some embodiments of the present invention, there isprovided a method wherein the determining comprises determining usingelectrophysiological measurements.

According to some embodiments of the present invention, there isprovided the method wherein the organ is a heart, and the dysfunction isarrhythmia.

According to some embodiments of the invention, the body tissuecomprises cardiac tissue.

According to some embodiments of the invention, the cardiac tissuecomprises a portion of the viable but reduced-innervation cardiactissue.

According to some embodiments of the invention, the body tissuecomprises non-cardiac tissue.

According to some embodiments of the invention, the body tissuecomprises neural tissue.

According to some embodiments of the invention, the determiningcomprises detecting portions of heart wall which lack electricalactivity.

According to some embodiments of the invention, ablating comprisesablating near regions of a heart wall where muscle died.

According to some embodiments of the present invention, there isprovided a method comprising correlating the determined reducedinnervation tissue with one or both of the identification of arrhythmicfoci and identification of reentrant loop, and ablating based on aresult of the correlating.

According to an aspect of some embodiments of the present invention,there is provided a method of organ mapping comprising: (i) identifyingportions of the organ with reduced nervous control; and (ii) arrangingthe portions in a map.

According to some embodiments of the present invention, there isprovided a method according to claim 25, also comprising identifyingportions of the organ that are viable and portions of the organ that arenot viable.

According to some embodiments of the present invention, there isprovided a method comprising identifying portions of the organ withreduced ganglion control.

According to some embodiments of the present invention, there isprovided a method comprising diagnosing an illness of the organ based onthe map.

According to some embodiments of the invention, the diagnosing comprisesidentifying portion of the organ at risk for causing or maintaining afunctional disorder.

According to some embodiments of the present invention, there isprovided a method comprising treating the organ based on the map.

According to some embodiments of the invention, the treating comprisesablating at least part of a portion of the organ with reduced nervouscontrol.

According to some embodiments of the invention, the treating comprisesselecting a pharmaceutical regimen based on the map.

According to some embodiments of the invention, identifying comprisesdual isotope radio imaging.

According to some embodiments of the invention, the organ is a heart.

According to some embodiments of the present invention, there isprovided a method comprising identifying portions of the heart musclewhich are hibernating, with at least some electrical activity but nomechanical activity.

According to some embodiments of the invention, the organ is a heart,and the diagnosing comprises identifying portion of the heart at riskfor causing or maintaining arrhythmia.

According to some embodiments of the invention, the organ is a heart,and the treating comprises selecting a pacing location or a pacing typebased on the map.

According to an aspect of some embodiments of the present invention,there is provided a map showing portions of a heart wall that aremechanically active but have reduced nervous control, stored on anon-volatile computer storage media.

According to an aspect of some embodiments of the present invention,there is provided a map showing portions of an organ anatomy that arefunctionally active but have reduced nervous control, stored on anon-volatile computer storage media.

According to an aspect of some embodiments of the present invention,there is provided apparatus for carrying out the method.

According to an aspect of some embodiments of the present invention,there is provided apparatus comprising circuitry configured to compare aviability image with a nervous control image and generate a map ofportions with viability and reduced nervous control.

According to an aspect of some embodiments of the present invention,there is provided a method of detecting or diagnosing a pathology due tounbalanced damage and/or functioning of body tissue, comprising: (i)measuring the distribution of functionality of a first affectedfunction; (ii) measuring the distribution of functionality of a secondaffected function; and (iii) identifying areas of unbalanced damage.

According to some embodiments of the invention, the measuring comprisesmeasuring using a nuclear medicine imager to detect differences infunctionality in regions smaller than 20×20×20 millimeters in volume.

According to an aspect of some embodiments of the present invention,there is provided a method of treating cardiac arrhythmia in a heart,comprising: (i) determining an imbalance between cardiac tissueinnervation and viability; and (ii) ablating tissue to change thebalance between innervation and viability to reduce prevalence ofarrhythmia in the heart.

According to some embodiments of the invention, the determining animbalance comprises determining a potential mode of arrhythmiccontraction within a region of imbalance between cardiac tissueinnervation and viability.

According to some embodiments of the invention, the changing of thebalance comprises ablation of tissue within a region of participating inthe potential mode of arrhythmic contraction.

According to an aspect of some embodiments of the present invention,there is provided a system for treating dysfunction of an organ,comprising: a modeling unit, configured to receive functional image dataof the organ and determine therefrom a model describing: regions oforgan viability, and regions of reduced organ innervation; a treatmentplanning unit, configured to: match the model with a disease-treatmenttemplate, according to a disease condition modeled in the template, andprovide a treatment plan associated with the template, according to thematch.

According to some embodiments of the invention, the treatment plancomprises an indication selecting a portion of body tissue for ablation.

According to some embodiments of the invention, the organ is a heart,and the dysfunction is arrhythmia.

According to some embodiments of the invention, the body tissuecomprises cardiac tissue.

According to some embodiments of the invention, the cardiac tissuecomprises a portion of the viable but reduced-innervation cardiactissue.

According to some embodiments of the invention, the body tissuecomprises non-cardiac tissue.

According to some embodiments of the invention, the body tissuecomprises neural tissue.

According to some embodiments of the invention, the modeled diseasecondition comprises an indication of potential arrhythmia.

According to some embodiments of the invention, the organ is an organ ofthe gastrointestinal tract.

According to some embodiments of the invention, the organ is thestomach.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

As will be appreciated by one skilled in the art, aspects of the presentinvention may be embodied as a system, method or computer programproduct. Accordingly, aspects of the present invention may take the formof an entirely hardware embodiment, an entirely software embodiment(including firmware, resident software, micro-code, etc.) or anembodiment combining software and hardware aspects that may allgenerally be referred to herein as a “circuit,” “module” or “system.”Furthermore, aspects of the present invention may take the form of acomputer program product embodied in one or more computer readablemedium(s) having computer readable program code embodied thereon.Implementation of the method and/or system of embodiments of theinvention can involve performing or completing selected tasks manually,automatically, or a combination thereof. Moreover, according to actualinstrumentation and equipment of embodiments of the method and/or systemof the invention, several selected tasks could be implemented byhardware, by software or by firmware or by a combination thereof usingan operating system.

For example, hardware for performing selected tasks according toembodiments of the invention could be implemented as a chip or acircuit. As software, selected tasks according to embodiments of theinvention could be implemented as a plurality of software instructionsbeing executed by a computer using any suitable operating system. In anexemplary embodiment of the invention, one or more tasks according toexemplary embodiments of method and/or system as described herein areperformed by a data processor, such as a computing platform forexecuting a plurality of instructions. Optionally, the data processorincludes a volatile memory for storing instructions and/or data and/or anon-volatile storage, for example, a magnetic hard-disk and/or removablemedia, for storing instructions and/or data. Optionally, a networkconnection is provided as well. A display and/or a user input devicesuch as a keyboard or mouse are optionally provided as well.

Any combination of one or more computer readable medium(s) may beutilized. The computer readable medium may be a computer readable signalmedium or a computer readable storage medium. A computer readablestorage medium may be, for example, but not limited to, an electronic,magnetic, optical, electromagnetic, infrared, or semiconductor system,apparatus, or device, or any suitable combination of the foregoing. Morespecific examples (a non-exhaustive list) of the computer readablestorage medium would include the following: an electrical connectionhaving one or more wires, a portable computer diskette, a hard disk, arandom access memory (RAM), a read-only memory (ROM), an erasableprogrammable read-only memory (EPROM or Flash memory), an optical fiber,a portable compact disc read-only memory (CD-ROM), an optical storagedevice, a magnetic storage device, or any suitable combination of theforegoing. In the context of this document, a computer readable storagemedium may be any tangible medium that can contain, or store a programfor use by or in connection with an instruction execution system,apparatus, or device.

A computer readable signal medium may include a propagated data signalwith computer readable program code embodied therein, for example, inbaseband or as part of a carrier wave. Such a propagated signal may takeany of a variety of forms, including, but not limited to,electro-magnetic, optical, or any suitable combination thereof. Acomputer readable signal medium may be any computer readable medium thatis not a computer readable storage medium and that can communicate,propagate, or transport a program for use by or in connection with aninstruction execution system, apparatus, or device.

Program code embodied on a computer readable medium may be transmittedusing any appropriate medium, including but not limited to wireless,wireline, optical fiber cable, RF, etc., or any suitable combination ofthe foregoing.

Computer program code for carrying out operations for aspects of thepresent invention may be written in any combination of one or moreprogramming languages, including an object oriented programming languagesuch as Java, Smalltalk, C++ or the like and conventional proceduralprogramming languages, such as the “C” programming language or similarprogramming languages. The program code may execute entirely on theuser's computer, partly on the user's computer, as a stand-alonesoftware package, partly on the user's computer and partly on a remotecomputer or entirely on the remote computer or server. In the latterscenario, the remote computer may be connected to the user's computerthrough any type of network, including a local area network (LAN) or awide area network (WAN), or the connection may be made to an externalcomputer (for example, through the Internet using an Internet ServiceProvider).

Aspects of the present invention are described below with reference toflowchart illustrations and/or block diagrams of methods, apparatus(systems) and computer program products according to embodiments of theinvention. It will be understood that each block of the flowchartillustrations and/or block diagrams, and combinations of blocks in theflowchart illustrations and/or block diagrams, can be implemented bycomputer program instructions. These computer program instructions maybe provided to a processor of a general purpose computer, specialpurpose computer, or other programmable data processing apparatus toproduce a machine, such that the instructions, which execute via theprocessor of the computer or other programmable data processingapparatus, create means for implementing the functions/acts specified inthe flowchart and/or block diagram block or blocks.

These computer program instructions may also be stored in a computerreadable medium that can direct a computer, other programmable dataprocessing apparatus, or other devices to function in a particularmanner, such that the instructions stored in the computer readablemedium produce an article of manufacture including instructions whichimplement the function/act specified in the flowchart and/or blockdiagram block or blocks.

The computer program instructions may also be loaded onto a computer,other programmable data processing apparatus, or other devices to causea series of operational steps to be performed on the computer, otherprogrammable apparatus or other devices to produce a computerimplemented process such that the instructions which execute on thecomputer or other programmable apparatus provide processes forimplementing the functions/acts specified in the flowchart and/or blockdiagram block or blocks.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings and images.With specific reference now to the drawings in detail, it is stressedthat the particulars shown are by way of example, and for purposes ofillustrative discussion of embodiments of the invention. In this regard,the description taken with the drawings makes apparent to those skilledin the art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1 is a schematic showing of cardiac tissue including dead zones,living zones hibernating zones and zones with reduced nervous control;

FIG. 2 is a flowchart of a method of identifying cardiac tissue zoneswith reduced nervous control, in accordance with some exemplaryembodiments of the invention;

FIG. 3A is a flowchart of a method of radioimaging to find cardiac zoneswith reduced control, in accordance with some exemplary embodiments ofthe invention;

FIG. 3B is a flow chart of a method for processing functional images toidentify and/or locate one or more ANS components (such as ganglia),according to some exemplary embodiments of the invention;

FIG. 4 is a flowchart of a method of finding cardiac zones with reducedcontrol, in accordance with some exemplary embodiments of the invention;

FIG. 5 is a flowchart of a method of reducing cardiac arrhythmia and/orassessing risk and/or diagnosing and/or therapy planning, in accordancewith some exemplary embodiments of the invention;

FIG. 6 is a schematic showing of a system for identifying tissue zoneswith reduced nervous control, in accordance with some exemplaryembodiments of the invention;

FIG. 7 is a set of nuclear medicine images showing tissue zones withreduced nervous control, in accordance with some exemplary embodimentsof the invention;

FIG. 8 is a set of nuclear medicine images showing tissue zones withreduced nervous control, in accordance with some exemplary embodimentsof the invention;

FIG. 9 is a set of nuclear medicine images showing left atrium tissuezones with scarring and/or abnormal nervous control, according to someexemplary embodiments of the invention;

FIG. 10 is a set of nuclear medicine images showing left ventricletissue zones with scarring and/or abnormal nervous control, according tosome exemplary embodiments of the invention; and

FIGS. 11, 12 and 13 are sets of nuclear medicine images showing leftatrium tissue zones with scarring and/or abnormal nervous control,according to some exemplary embodiments of the invention.

FIGS. 14A, 14B, 14C and 14D illustrate a disease mode of a heart, forwhich activity imaging provides an understanding which guides awell-localized application of treatment, according to some exemplaryembodiments of the invention;

FIG. 15 is a block diagram of a model ANS modeling system/unit, inaccordance with some exemplary embodiments of the invention; and

FIG. 16 is a block diagram of a model analysis and treatment planningsystem/unit, in accordance with some exemplary embodiments of theinvention.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to detectionof tissue with reduced and/or mismatched innervation, and moreparticularly, but not exclusively, to detecting viable cardiac tissuethat lacks nervous control.

Overview

A broad aspect of some embodiments of the invention relates to imagingof tissue in a plurality of aspects comprising aspects related to tissuefunctioning. In some embodiments, two, three, four or more functionalaspects are imaged or otherwise measured. In some embodiments, thefunctional aspects are registered to one another in a map, such that themap, in some respects, may be said to “image the pathology” of adiseased organ.

A broad aspect of some embodiments of the invention relates to tissuewith a mismatch among a plurality of functional aspects such asinnervation and viability; for example: tissue with damaged innervationand intact (or less damaged) viability and/or tissue with damagedviability but intact (or less damaged) innervation. In some embodimentsof the invention matching and/or mismatching among multiple functionalaspects of a tissue is related to, the functional aspects including, forexample, innervation, viability, ischemia, contractility, perfusion,metabolism, and/or another function aspect of tissue. In someembodiments a plurality of functional aspects is related to, forexample, two, three, four, five, six, seven, or more functional aspects.In some embodiments of the invention, function is measured, for example,by nuclear imaging of the uptake of a radiolabel, the uptake of which isproportional to a functional aspect such as metabolism, innervation,and/or viability. In some embodiments, a measurement of blood flowvolume is converted to a measure of, for example, ischemia or perfusion.In some embodiments, dynamic imaging such as fluoroscopy is used todetermine contractility. In some embodiments, another imaging modalityis used, optionally together with a tag or tracer suitable forindicating a particular functional aspect of the tissue.

Some embodiments of the invention relate to cardiac tissue, but otherembodiments are used in other tissue types. In general, in an exemplaryembodiment of the invention, the spatial properties of areas withreduced innervation are compared with those of areas with reducedviability. Non-overlapping areas and/or boundaries between such areasand/or with healthy (and/or balanced) tissue may be especiallyproblematic. For example, in the heart, boundary areas are hypothesizedto generate and/or maintain arrhythmia.

In an exemplary embodiment of the invention, diagnosis and/or treatmentplan is based on the idea that areas with mismatched viability andinnervation tend to respond differently than matched tissue to demandson the tissue. The differences may be, for example, in a time profile ofa response to demand or differences in an amplitude profile of aresponse to demand. In electrically excitable tissue, such differencecan increase susceptibility to arrhythmia. In contractile tissue, suchimbalances may give rise to induction of ischemia due to imbalancebetween oxygen/nutrients supply and the local metabolic demand. Incontractile structure such imbalances can generate an uncoordinated typeof heart contraction increasing inefficiency in propelling the blood outof a heart chamber. Potentially, uncoordinated contraction can lead toprogressively poorer perfusion of the heart and increasinglyuncoordinated contraction (for example, as a result of ischemia).Potentially, this feedback cycle can end in death of an individual. Inhealthy and/or some matched tissues, when the response of differentparts is different, the nervous control system (and/or another bodysystem) acts to coordinate the work and/or balance the responses.However, in mismatched tissue, such balancing may be faulty and lead tovarious pathologies such as arrhythmia, high stress, ischemia,inefficient metabolism, uncoordinated motion and/or inefficientcontraction.

In an exemplary embodiment of the invention, such mismatch detection isused to assess the effect of diffuse illnesses, such as nerve damagecaused by diabetes (e.g., or other causes such as storage diseases,degenerative diseases and hypertension). In such an example, in anexemplary embodiment of the invention, tissue (e.g., cardiac orotherwise) is imaged with two tracers, one for detecting nerve activityand one for detecting tissue functionality (e.g., metabolism). Areas ofmismatch are optionally flagged as potentially problem causing and/or tobe the target of treatment and/or monitoring. In the case of gastricparesis due to diabetes, a possible finding (for which investigativeimaging and/or processing may be performed) will be that the synapticactivity of the autonomic nervous system is (e g, uniformly) decreasedin certain conditions while the local motility is also further decreased(match); however, in certain cases, the gastric activity (e.g.,motility) is under reduced control of the autonomic nervous system andirregular and/or spatially non-uniform motility activity appears. Inanother example, a mismatch between gastric (and/or other GI) contractactivity and gastric (and/or other GI) digestion secretion appears.

An aspect of some embodiments of the invention relates to the effect ofunbalanced damage to body tissue, where such unbalanced (or mismatched)damage relates to the selective damage of a first tissue component,relative to that of a different tissue component. Optionally, damage toa tissue component comprises a functional aspect, for example, due toloss of innervation. In an exemplary embodiment of the invention, onecomponent is a working component and/or function and the other componentis a control component and/or function. In other examples, the twocomponents are both of working type and/or both of control type. Oneexample is mismatched damage to nerve and muscle tissue. Another exampleis mismatched damage to different nerve types (e.g., sensing and controlnerves or efferent and efferent nerves, respectively). In an exemplaryembodiment of the invention, by providing high resolution functionalimaging, the fact of such selective damage can be determined and/orvisualized. In an additional example, the two tissue functions arekidney glomerular function and kidney hormonal sensitivity. Optionally,function is measured, for example, by the deposit, washout, and/oruptake of a radiolabeled marker that passes through the glomerulus.Optionally, hormonal sensitivity is measured, for example, by imaging ofhormonal receptor binding, where a radiolabeled hormone analog is bound.

In a more general example of some embodiments of the invention, onecomponent of tissue function is from a first group and a second from asecond group. For example, group I contains and is not limited to,muscle cell, fibrous tissue, endocrine tissue, exocrine tissue, skeletaltissue, connective tissue, neural tissue, parenchymal tissue of theliver, spleen, kidney, glomerular tissue of the kidney, and/or acinartissue of the salivary glands. For example, group II includes but is notlimited to muscle cell, fibrous tissue, endocrine tissue, exocrinetissue, skeletal tissue, connective tissue, neural tissue, parenchymaltissue of the liver, spleen, kidney, glomerular tissue of the kidney,and/or acinar tissue of the salivary glands.

In an exemplary embodiment of the invention, one or more of mapping,quantifying, diagnosing, planning to treat, and/or treatment ortreatment guidance for a pathology is based on the ability to mapmultitude of function in a region and the understanding that normalconditions relate to balanced function of all tissue components.Identification of the unbalanced (e.g., unmatched) situation, can enablethe physician or the technician to map, quantify, diagnose, plan atreatment and/or guide a treatment for a multitude of disease processes.It is particularly noted that control mechanisms, such as nervouscontrol, can serve to balance otherwise unbalanced function. Often lackof balanced behavior is due to or includes a component of nervousdamage.

It is noted that while the description has focused on unbalancing of twocomponents, unbalancing as detected and/or treated in accordance withsome embodiments of the invention can be in three or more dimensions aswell. Such multidimensional balance (or lack thereof) is the generalbalance of a multitude of functions. In a healthy tissue, all functionsare balanced (or can be balanced under suitable control) with all otherfunctions through the entire space of allowable and/or possible range.For example, body temperature, liver metabolism, renal function andheart function are all time varying. In healthy tissue these variationsare coordinated and compensate for each other so that together ahomeostasis is preserved. In a disease condition, an imbalance can causefailure of the homeostasis and/or require overwork by one or morecomponents leading to a disorder. In an exemplary embodiment of theinvention, such balance and/or lack of balance is detected by imaging,optionally over time, and searching for mismatches. Optionally oralternatively, such balance or lack of balance is detected by takingdata about tissue activity and searching for mismatching, for examplemismatch in spatial areas of behavior and/or mismatch in temporalresponse between areas and/or between physiological mechanisms.

Other examples of disordered and/or mismatched timing comprise patientswith certain forms of CNS disorder (Parkinson's disease, for example, ordepression). The ANS is potentially significant in controlling theconduction velocity, refractoriness, excitability and/or sustaining ofbrain circuits. Some modes of circuit control, when present, potentiallyunderlie, for example, disturbed behavior or mood: for example,depression (in relation, for example, to the limbic system) or a diseasesuch as Parkinson's syndrome (in relation, for example, to motorcontrol). Potentially, ANS system modulation impinging on the CNSaffects activity in such regions, and therefore influences thepropagation of electrical impulses in the brain. Damage to the controlANS system potentially comprises a lesion in some part of the gangliaand/or nerve fibers controlling the brain. This condition can lead, forexample, to the creation of a spatial dispersion (differences amongregions) in the electrophysiology of the brain. Such anisotropy in turnpotentially comprises a substrate within which new (possiblypathological) circuit activity patterns arise.

A propagating message can get lost in an area of such a pattern, forexample, due to circuit noise, altered conduction velocity, increasedlikelihood of encountering a refractory circuit element, or anotherreason.

Unbalanced damage to tissue components can arise from multiple reasonsincluding, but not limited to:

-   -   Different sensitivity of each component to a same chemical,        viral, pathogen stimuli.    -   The fact that certain tissue components are merely “cables” that        are pass through a host tissue undergoing damage. These “cables”        tissue components can include, for example, nerves, vessels,        tendons, fibers and/or lymphatic channels.    -   The fact that certain information is conveyed to and from a        tissue that is damaged and the information        generation/transmission is affected too. However, the effect of        the generated/transmitted information is located in region other        than those of the affected tissue, potentially giving rise to an        unbalanced effect of a single pathological event.    -   Different pathologies which occur at different times to nearby        tissues.

As noted, a particular example is where afferent neural pathways areaffected differently than other tissue components co located with them.For example, in the case of the heart: one can find (e.g., due to aprocess of ischemia, such as a heart attack) the formation of a fibroustissue replacing the normal contractile tissue (myocytes) of the heart,and the same process and/or the same fibrous response may also disruptneurons of the autonomic nervous system that traverse the affected areaof the heart. These neurons are usually of two types—efferent andafferent neurons, one or both of which may be damaged and/or damaged inan unbalanced manner. This differentiation is based, at least in part,on the direction of messaging of these neuron and/or type ofneurotransmitter found at tips thereof and/or existence of receptors(e.g., mechanoreceptors) therein. The afferent neurons conveyinformation from sensors within the tissue (e.g., distal to the damagedarea) and the efferent neurons bring messages from areas that areproximal to the damaged area. In some embodiments of the invention, whatis expected and/or detected and/or planned for is an upstream damage tothe afferent neural system and/or a downstream damage to the efferentsystem.

In some embodiments of the invention, a plurality of functions of anorgan system operate in different states of mutual balance or unbalancethrough different portions of their operating range. Optionally, atargeted scope of concern for functional balance (with respect todiagnosis and/or treatment) is confined to a sub-portion of thisoperating range. Optionally, this sub-portion reflects a diseased state.For example, due to a disease process, neural conduction within acertain part of the neural system is changed such that while operatingin a low conduction velocity regime, it is matched to the refractoryperiod. However, while operating in a fast conduction velocity regime,matching to the refractory period is lost, and two functions (forexample, stimulation and excitability) become unmatched.

Some examples shown below use imaging of sympathetic synapses and showthe effect of such lesions. It is noted that based on anatomicalknowledge regarding nerves and lesions, upstream and/or downstreamnervous damage is optionally estimated.

An aspect of some embodiments of the invention relates to detectingand/or treating a heart with zones having reduced nervous control,especially such zones that border with zones having normal nervouscontrol. In some cases, what is detected and/or treated are zones with agreater mismatch between viability and innervation that other zonesand/or borders between the two. In an exemplary embodiment of theinvention, such border and/or mismatched zones are suspected as actingas sources of arrhythmia, possibly due to a large dispersion ofelectrophysiological properties therein. Optionally, such zones areidentified and then ablated, for example to prevent and/or treatarrhythmia and/or to reduce its prevalence.

Some embodiments of the invention are based on the realization thatcardiac muscle tissue is controlled using several mechanisms, includingnervous control, hormonal control and effect of excitation by nearbytissue. In diseased tissue it has now been realized that control may becompromised. Moreover, tissue with compromised control may lie side byside with tissue with normal or less compromised control. This can causevarious pathologies. In one example, tissue with reduced nervous controldoes not react immediately when the heart changes workload, leading to areduced cardiac output and to significant differences in actionpotential shape. For example, some tissue may be refractory while nearbytissue is not. Furthermore, the inventors have discovered that suchtissue with compromised control and/or borders thereof may be bandshaped, which allows it to act as an alternative conduction pathway orreentrant conduction pathway for ventricular (or other) arrhythmia. Inanother example, noting that a typical stress response starts withnervous control and continues with hormonal control, the same tissuewhich did not react sufficiently to increased cardiac workload willreact or overreact to increased blood levels of hormones (e.g.,adrenaline). Such increased response may come, for example, because thecompromised tissue cannot have the hormonal effects modulated (e.g.,reduced) by nervous control and/or because such tissue may be overlysensitive to hormonal control as a compensation for lack of nervouscontrol.

As can be appreciated, tissue with comprised control may affect cardiacoutput, cardiac activation profile and stress distribution and/ormediate arrhythmia.

In an exemplary embodiment of the invention, identification of suchreduced control zones uses dual isotope radioimaging, with one isotopebeing used to identify metabolic activity and a second isotope used toidentify the activity of presynaptic neurons and/or the density ofreceptors for neurotransmitters and/or number of nerve endings. Zoneswhere there is metabolic activity but reduced activity of presynapticneurons may be considered to have reduced control. It should be notedthat a zone may have partial nervous control or no nervous control, aswell as full nervous control. In addition, there may be some variabilityin level of control between parts of the heart. Optionally, alsoganglions connected to the heart tissue are imaged and the level ofactivity therein is used. In some embodiments, the level of activityhelps determine the “driving force” behind the organ. In someembodiments, the level of activity is used to correct for an assumptionof the effect of density of receptors. For example, a highly activeganglion may compensate for lower density of nerve endings and viceversa (lack of ganglion activity may indicate substantially inoperativenerve endings).

In some embodiments of the invention, the image identifies areas at theborder between innervation and the denervation tissue of the heart,which areas may be prone to having a large dispersion ofelectrophysiological (and/or electromechanical) properties, for example,those that are usually under autonomic nervous modulation.

In an exemplary embodiment of the invention, a patient is treated, forexample, by ablating problematic zones. Optionally or alternatively,long conduction pathways are ablated to split them. Optionally oralternatively, when pacing, pacing locations are selected according tothe degree of tissue control. For example, anti-arrhythmic pacing may beselected to be in a reduced control zone. Optionally or alternatively,drug treatment (e.g., beta blockers) may be selected according to anexpected amount of tissue control. Optionally, ablation is of a cardiacganglion residing at a higher level than a problematic ganglion.Potentially, ablation of a higher-level ganglion act to homogenize inputto an overall region, such that it is less vulnerable to entering a modeof mismatched activity. It should be noted that this potentiallycomprises a sacrifice of some level of control, in order to avoid theoccurrence of a worse condition, such as an arrhythmia.

Denervation ablation, in some embodiments, comprises, for example,ablation of innervation along blood vessels. Optionally, ablation isalong wall surfaces (inner or outer) of less than, for example, 1×1 mm²,3×3 mm², 6×6 mm², 15×15 mm², 40×40 mm², 80×80 mm², or another greater,lesser, or intermediate surface size. Optionally, ablation is within avolume of less than, for example, 1×1×1 mm³, 3×3×3 mm³, 8×8×8 mm³,20×20×20 mm³, 40×40×40 mm³, or another greater, lesser, or intermediatevolume size. Ablation is, for example, in the organ to be treated, toanother organ which has an effect carried to the organ requiringtreatment by a neural pathway, and/or to another organ which has aneffect carried to the organ requiring treatment by a non-neural pathway.

In some cases, treatment may be selected even without imaging. Forexample, having identified that reduced control tissue may be a cause ofan arrhythmia, in a patient where arrhythmia is triggered by stress orstopping of stress, ablation of cardiac tissue surrounding electricallydead zones may be carried out, even without identifying such zones aslacking nervous control. For example, if there is a large infarct area,a plurality of point ablations may be carried out along itscircumference, so as to break up conduction pathways in reduced controltissue, which may be located therein.

It is noted that in some cases the portion of the heart which is notviable may be small or non-existent. Thus, a heart may include areaswith reduced nervous control and not have nearby areas with reducedviability. A possible treatment for such areas is to ablate them so asto avoid a mismatch between control and viability.

Another possible treatment for such areas (e.g., where areas that areunder control are adjacent to areas that are not under control;innervated adjacent to denervated areas) is as follows. In such areas,the existence of possible dispersion of properties can bring about asignificant complication (for example in the case of electricalconducting tissue that is exposed to sympathetic stimuli, the innervatedtissue will have a faster conduction velocity and a shorter refractoryperiod instantaneously with the arrival of the neural input; however,the denervated tissue will not change its electrophysiologicalproperties as the direct sympathetic innervations is disrupted(denervated). The danger of this situation is the appurtenant spatialdispersion of electrophysiological properties which is a potential causefor the formation of reentrant arrhythmias. A treatment in this case canbe the formation (e.g., by ablation) of a boundary line between theinnervated and the denervated regions such that electrical signal willnot be able to propagate from one section to the adjacent section.Additionally or alternatively, administration of a drug, for example oneknown in the art to have conduction velocity effects, potentiallychanges conduction velocity, for example, reducing it by up to 50%.Potentially, the reduction in speed alters the timing of events in thetissue such that a threshold for entering a dangerous mode of operation(for example, arrhythmia), is raised.

It is noted that while this description is focused on the heart, as itis an important organ, other organs may be imaged and/or treated aswell, for example, the stomach, which can also include zones which areviable and are lacking sufficient nervous control.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details of construction and the arrangement of thecomponents and/or methods set forth in the following description and/orillustrated in the drawings and/or given in the Examples. The inventionis capable of other embodiments or of being practiced or carried out invarious ways.

Referring now to the drawings, FIG. 1 is a schematic showing cardiactissue 100 including dead zones, living zones, hibernating zones andzones with reduced nervous control. In the example shown, an infarctarea 102 is dead and is substantially fibrous tissue (e.g., afterhealing). An area 104 indicates a portion which has reduced or nonervous control. An area 106 shows an overlap between areas 104 and 102where tissue is not viable and also has no nervous control. Generally,dead tissue 102 will not be able to have nervous control. However, insome cases, nerves serving the area may be viable (e.g., the servingganglions are viable) and if the dead tissue recovers and/or is treatedto recover, such tissue may or may not have nervous control.

An area 108 indicates healthy tissue. An area 110 indicates tissue whichis mechanically and/or electrically healthy, but which lacks (or hasreduced) nervous control and/or which has more damage to the nervouscontrol mechanism than to its organic function. This process ofselective impairment of different co-located tissues is the hallmark ofcertain disease processes such as diabetes, storage disease, vascular,neoplastic, toxic materials, infectious disease, and many other diseasestates. The underlying cause may be the selective damage to nerve tissueand/or damage to nerve fibers in one location which cause impairednervous control in another.

It is noted that also the opposite type of mismatch may be of interest,tissue with a greater reduced viability than nervous control.

In these disease processes, the susceptibility of a component of atissue to the pathophysiologic process of the disease is often highlyvariable although all components are co-located. For example, indiabetes is it well known that neural tissue is more sensitive thanother tissues to the microvascular damage caused by long-standingdiabetes. Furthermore, the specific neural damage of diabetes is furthermore specific in sub-group of nerves that have a much higher sensitivityto diabetes damage (at times a threefold higher sensitivity). Forexample, in a long standing diabetic patient one may find preservationof most of the peripheral neuronal function with a very specific damageto nerves conducting vibration information, or to nerves conductingtemperature information.

Specific damage to very specific tissue components can also be seen inother diseases, such as viral diseases (or autoimmune responsesthereto), which can, for example, affect specific neurons in specificcenters of the brain (for example in the visual cortex, or in theauditory canal).

In some cases, the disease-specific damage to specific tissue componentscan be further sub-divided by location. This type of behavior mayexplain very discrete loss of function of one component as compared to(or in addition to) the generalized loss of function in other diseasepathology (for example blunt trauma). Such an area may act as a focusfor imbalanced control of bodily system.

In an exemplary embodiment of the invention, the etiology of suchdiseases and/or potential consequences and/or treatment is determined byimaging to determine unbalanced regions and/or their relationship tobalanced regions and/or the effect of such regions and/or boundariesthereof on systemic function of organs and/or the body.

An area 112 indicates an elongate section with reduced nervous controlnear and/or overlapping area 102 which is substantially dead. As notedherein, such an area may act as a reentry circuit for certain types ofarrhythmia.

An area 114 indicates a hibernating region, which is damaged by ischemiaand so lacks mechanical activity and possibly some measure of electricalactivity, but may also lack some or all nervous control. Even if not adanger at a current time, as such tissue recovers danger may occur.

In an exemplary embodiment of the invention, the size of the damagedareas and/or mismatch areas is relatively small, for example, beingbetween 10×10 mm and 100×100 mm, and/or, for example, between 10×10 and50×50 mm Optionally, a maximal extent of such a region is less than 70mm, 50 mm, 30 mm or 20 mm. In some embodiments, however, smallermismatched regions are detected, for example, between 1×1 mm and 10×10mm in extent. Areas larger than 100×100 mm may also be detected.

In an exemplary embodiment of the invention, the distance between thecenters of the areas is between 10 and 100 mm. In some embodiments, theareas are a patchwork of interleaved areas, which may be, for example,between 10×10 and 200×200 mm in size. Such a patchwork may include, forexample, between 2 and 20 areas; for example, 3, 5, 6, 8 or anintermediate or greater number of areas with mismatched viability andnervous control.

While FIG. 1 shows a plan view of muscle tissue 100, it is noted thatdead zones and zones with reduced nervous control may occur at differentdepths of tissue. So a same-tissue location may have one layer withviability and nervous control, a second layer with viability but nonervous control, a third layer with nervous control (e.g., if colonizedby stem cells) but no viability and/or a fourth layer with neitherviability nor nervous control.

It is also noted that some parts of the heart may have intermediatelevels of nervous control rather than just binary levels.

FIG. 2 is a flowchart 200 of a method of identifying cardiac tissuezones with reduced nervous control, in accordance with some exemplaryembodiments of the invention.

At 202, live portions of muscle are detected, for example, usingradioimaging techniques (e.g., FIG. 3A).

At 204, portions of heart wall with reduced innervation are detected,for example by detecting a level of innervation and identifying areaswith a low such level. Optionally, radioimaging techniques (e.g., FIG.3A) are used for such detecting.

At 206, a mismatch between non-viable areas and non-controlled areas isdetermined, for example, by correlating and/or otherwise comparing a mapof viability and a map of nervous control.

In some embodiments of the invention, nervous control is furtherdetermined by mapping ganglions that control the muscle 208. Optionally,the level of activity in a ganglion is used to compensate for aperceived level of nervous control.

While, in general, nervous control is not binary, it is further notedthat for various reasons the amount of nervous control at differentparts of the heart may be different and/or may be detected as beingdifferent. Optionally, a map indicating allowed ranges for each portionof the heart is used to determine if a detected difference is a realdifference or within normal parameters. Optionally, comparison to apreviously acquired map of the patient is used. Optionally oralternatively, a heart-wide threshold (sharp or fuzzy) method is used toindicate lack or reduced or normal control levels.

It is noted that the viability of different parts of the heart may vary,especially imaging thereof may vary. As described for control, a map orthreshold may be provided for viability determination.

Optionally, as described below, acquired data are normalized.

At 210, a map of the heart is generated indicating areas with a mismatchbetween nervous control potential (and/or activity) and viability.Optionally, a plurality of levels of control is indicated, for example,2, 3, 4, 5, 10, or smaller, intermediate, or greater number of levels ofcontrol. Optionally or alternatively, a plurality of levels of viabilityis indicated, for example, 2, 3, 4, 5, 10, or smaller, intermediate, orgreater number of levels of viability. In some embodiments, only typesof areas are shown and/or overlaid on the map; for example, “normal”,“dead” and “live but uncontrolled”. Optionally, other data, for example,relating to ischemia, are shown as well. Optionally, such data are usedto assess the risk of a location reacting inappropriately to excitationand/or stress and/or nervous control and/or hormonal control and/or loadon heart and/or a treatment.

Optionally, at 212, various data, such as EP (electrophysiology) dataare overlaid on the map. An example of such EP data includes areas thatare suspected of being arrhythmia reentrant circuits and/or arrhythmiafoci.

In an exemplary embodiment of the invention, the map is a highresolution map, for example with a resolution of better than 5millimeters, 3 millimeters, and/or 2 millimeters. Optionally oralternatively, the map discriminates between different layers in thecardiac muscle wall. Optionally, the wall mapped is a ventricular wall,for example, the left ventricle. Optionally or alternatively, the wallis an atrial wall, for example, of the left atrium or the right atrium.

In an exemplary embodiment of the invention, the detected reducedcontrol viable regions are non-blob shaped and/or include non-blobregions. For example, a blob may be an area which can enclose a 20 mm×20mm or 30 mm×30 mm circle and may be generally convex. In contrast, thedetected areas may be, for example, elongate or arc shaped, for examplewith a length:width ratio of at least 1:5, 1:10, or more.

FIG. 3A is a flowchart 300 of a method of radioimaging data processing,in accordance with some exemplary embodiments of the invention, whichuses a model of the heart to localize radiation emissions to heart wallsand then determine uncontrolled viable tissue therein. While in someembodiments of the invention, the method shown in U.S. PatentApplication Publication No. 2009/0201291, the disclosure of which isincorporated herein by reference, is used for image reconstruction; inothers, a different method, for example the following method, may beused. In any case, it is noted that in some embodiments, the methodcomprises substantially acts 312-314: reconstructing two images andcomparing them. The images may be provided in various ways, for example,as described below.

At 302 a model of the heart is provided. Such a model is optionallygenerated using a CT imager. In an exemplary embodiment of theinvention, the model is a 4-D model which includes different shapes fordifferent parts of the cardiac cycle.

At 304, radioactive emissions are collected from the body. This may bedone, for example, before, during and/or after model provision.Optionally, the data acquisition is binned or gated according to cardiaccycle (e.g., using an ECG sensor to indicate state in cycle). In anexemplary embodiment of the invention, emissions are generated by firstinjecting the patient with two tracers, one which is selectively takenup by viable tissue (e.g., Tc-99 in Sestamibi) and one which isselectively taken up by nerve endings or tissue which collectsadrenaline (e.g., mIBG with I-123 or I-131).

At block 306, a template for reconstructing the heart wall is selectedand/or otherwise generated. Block 306 may be carried out before, duringand/or after data collection. In an exemplary embodiment of theinvention, the template is an oversize template, for example, redefiningthe wall thickness to be a factor of between 1.1 and 2 of the thicknessindicated in the model. In an exemplary embodiment of the invention,this factor is a function of the thickness of an imaged (e.g.,reconstructed nuclear image) portion of the heart. For example, thetemplate thickness of the left ventricle is set to be a factor of about1.2 of the thickness of the left ventricle. Optionally or alternatively,the thickness of the right ventricle wall is set to be a factor of about0.7. Factors of about 0.5 are optionally used for the atrial walls. Itis noted that these factors are generally oversize with respect to thetrue wall thickness.

In an exemplary embodiment of the invention, the template is generatedby defining a first shape which fits inside the model and defining asecond shape which encloses the model and defining the template (wallsof interest) as lying between the two shapes.

At block 308, a correspondence between the template and the emissiondata are provided. For example, such a correspondence may be 3-D or 4-D.Optionally, the template is resized and registered to match the apparentsize of the heart. Optionally, this resizing uses one or more landmarksin the heart, for example, the left ventricle, which are acquired byreconstructing an image of the heart using the acquired emission data.Optionally or alternatively, other registration cues are used, forexample, the right ventricle, the liver or torso. Optionally oralternatively, an iterative reconstruction process is used with aninitial guess for the template registration being provided (e.g.,manually) and then the reconstruction is repeated to converge on thetemplate.

In one example, an average image (average between diastole and systole)is computed and used for registration.

In one example, the image (and/or model) of the heart is manuallysegmented, for example, to indicate the left atrium.

At 310, emissions from locations that match the template are collectedand used to reconstruct one or two images. If the template is 4-D, a 4-Dimage is optionally reconstructed. Optionally, for analysis, a series ofimages of the heart are integrated—for example, averaged—with the modelbeing used to define a mapping between different parts of the images atdifferent times.

At 312, two separate images are reconstructed, one for viability and onefor nervous control. Alternatively, a single image is reconstructed,with different tracers being tagged differently in the same image. Apotential advantage of first reconstructing one image and then twoimages, is that the combined data may be more plentiful and may be usedto more accurately reconstruct the shape of the heart. Then, the datamay be separated into two images and/or layers on an image.

In some embodiments, one or both of the images are previously acquired.For example, in some cases a CT image, MRI image, and/or fluoroscopyimage may be used to provide a viability image, optionally also actingas a basis for a model as described above. Optionally or alternatively,an image of fiber zones (for example, acquired as described in U.S.Provisional Patent Application No. 61/925,669 filed Jan. 10, 2014 titled“DETECTION OF SCAR AND FIBROUS CARDIAC ZONES”), is used as a viabilityimage.

At 314 the two images are compared and analyzed, for example, togenerate indications of sections which are both viable and notsufficiently controlled.

At 316, the values of the image(s) are optionally normalized along ascale between maximum and minimum. A threshold is optionally defined(e.g., 15%), below which an area is assumed to be non-active and/or notsuitably controlled. Optionally, different thresholds are provided fordifferent parts of the heart and/or based on a mapping of ganglionicactivity.

Optionally, in the image, the wall thicknesses are corrected accordingto an average wall thickness. It is noted that some parts of the heartmay be reconstructed so that a muscle wall thickness spans only a singlevoxel. In some cases, the identification of problematic zones isincludes also a depth coordinate relative to the wall surfaces e.g.,near inner surface, near outer surface, in mid area, spanning surface).

Various data may be overlaid on the reconstructed image, for example,data from the model or data from other imaging modalities. Inparticular, electrical measurement data may be overlaid and images ofimplants may be overlaid.

Reference is now made to FIG. 3B which is a flow chart of a method forprocessing functional images to identify and/or locate one or more ANScomponents (such as ganglia), according to some exemplary embodiments ofthe invention.

A branch of the flowchart of FIG. 3B begins, and in some embodiments ofthe invention, at block 352, functional imaging modality data and/orimages are received.

The data and/or images comprise, for example, a D-SPECT image and/orother images. Received images, in some embodiments, are of a body part;for example: a torso, abdomen, heart, or another body part, according tothe scanning protocol selected. The body part, in some embodiments,includes nervous system tissue to be imaged, and/or the innervated organitself. For example, nerve tissue comprises GPs of the heart, intestinesand/or another organ. Optionally, the functional images include regionsof activity that denote nerve tissue such as a GP made detectable, forexample, by uptake of a radiotracer such as mIBG. In some embodiments, atwo tracers are used; for example, first tracer such as mIBG to labelactivity, and a second tracer to image tissue vitality.

Optionally, functional data is collected from a body part that hasregions where nerve activity is expected, and regions where nerveactivity is not expected. For example, during imaging of the heart, datadenoting nerve activity is expected from the heart wall and/orsurrounding tissues, and no nerve activity is expected from inside theblood-filled hollow chambers. Potentially, noise is received from areascorresponding to the inside of the heart chamber, though no trueactivity is expected. Optionally, the noise is removed from thefunctional data based on the corresponding anatomical image; forexample, after image registration. Optionally, intensity denoting noisewithin blood- or other fluid-filled chambers and/or vessels is removed.For example, intensity readings of the functional data corresponding toheart chambers and/or surrounding blood vessels are removed by applyingone or more image mask on functional image. In some embodiments,fluid-filled chamber noise is used in obtaining a noise estimateapplicable to other tissue locations.

In some embodiments of the invention, at block 354, an anatomical regionis extracted from the image. Optionally, tissue image regions(potentially containing nerve structures) are segmented from hollowspaces (non-innervated, but potentially containing fluid). For example,the wall of the left ventricle (LV) and/or the hollow space within theLV is extracted. Optionally, the extracted region is a layer of tissue,such as the tissue layers forming the LV wall, instead of, for example,the LV including the hollow chamber inside the LV. In exemplary cases ofkidney imaging, the walls of the renal artery are extracted and/or theinside of the artery is extracted. When imaging other organs, dominantportions of the organ are optionally selected.

In some embodiments of the invention, at block 356, one or moreregistration cues are extracted from the image. Potential sources ofregistration cues include, for example, the organ of interest, and/orsurrounding anatomical structures. Particular examples include the LVaxis, liver, heart septum, RV, and/or torso. Optionally, registrationcues are used to match anatomical images with functional images, and/orto match anatomical images during a physiological cycle, such as thecardiac cycle.

Another branch of the flowchart of FIG. 3B begins, and in someembodiments of the invention, at block 358, anatomical image modalitydata and/or images are received. Anatomical image modality datacomprises data obtained, for example, from a CT, MRI, 3D ultrasound, 2Dultrasound, fluoroscope, or by another modality. The anatomical imagedenotes the structure of the tissue and/or organ innervated by nervetissue, such as a GP. The anatomical image denotes the tissue and/ororgan structure corresponding to the location of nerve tissue such as aGP. The anatomical images, in some embodiments, contain both the nervetissue to be functionally imaged and the innervated organ.Alternatively, anatomical data is received that is not personalized tothe patient, for example, from a general anatomical model.

Optionally, anatomical data from an anatomical imaging modality isreceived to reconstruct an anatomical image of a region of a body of apatient. Optionally, the region comprises a portion of at least oneinternal body part which borders on a target nerve tissue.

The anatomical images and the functional images denote correspondingregions of the body containing the GPs for identification and/orlocalization. For example, both modalities are employable to takepictures of the heart, kidney, or other organs. To image GPs of theheart, for example, anatomical and/or functional images of the heart areobtained. To image GPs of the kidney, in another example, anatomicaland/or functional images of the kidney, renal artery and/or aorta areobtained.

In some embodiments of the invention, at block 360, images correspondingto different times during a dynamic cycle are optionally extractedand/or acquired. For example, for the heart, images are extracted alongthe cardiac cycle. Periods selectable along the cardiac cycle forextraction include, for example, the end diastolic volume (EDV) and/orthe end systolic volume (ESV). In another example: for the bladder,images are optionally extracted corresponding to a full bladder and anemptying bladder.

In some embodiments, the average image is computed, for example, as(EDV+ESV)/2.

In some embodiments of the invention, at block 362, one or more imagesare segmented. Segmentation, in some embodiments, is fully automatic. Insome embodiments, segmentation requires or potentially involves manualuser intervention.

In some embodiments of the invention, at block 364, an anatomical regionis extracted. Optionally, the anatomical region corresponds to theanatomical region extracted at block 354. Optionally, the anatomicalregion is extracted from the segmented image of block 362.

In some embodiments of the invention, at block 366, one or moreregistration cues are extracted from the image. Potential sources ofregistration cues include, for example, the organ of interest, and/orsurrounding anatomical structures. Particular examples include the LVaxis, liver, heart septum, RV, and/or torso.

The branches of the flowchart merge, and in some embodiments of theinvention, at block 368, the functional images or data and theanatomical images or data are registered. Optionally, the images areregistered based on alignment of the extracted anatomical regions ofblocks 354 and 364. Registration is performed manually, automaticallyand/or semi-automatically.

Optionally, registration takes into account organ dynamics, for example,heart movement. As examples: anatomical images during the dynamic cycleare registered, and/or functional data are corrected for the dynamicmovement. As a particular example: intensity readings within the heartchamber are corrected to association with nearby moving heart wall.

In some embodiments of the invention, at block 370, image masks aregenerated based on the anatomical image and/or data. Optionally, theimage masks direct processing and/or visual display of the nerve tissueto specific locations of the image located within the image masks. Forexample: GPs are displayed and/or processed within the volume of anapplied image mask, GPs outside the volume of the image mask are notprocessed and/or displayed, and/or GPs outside the volume of the imagemask are processed and/or displayed differently than those GPs insidethe image mask.

Optionally, the anatomical images are processed to generate the imagemask corresponding to dimensions of at least one internal body part, forexample, the walls of the chambers of the heart. For example, adimension of an internal body part of the specific patient is calculatedand used to define the mask.

Optionally, the image masks are selected and/or defined for tissuesurrounding a hollow chamber. As examples, image masks are defined basedon:

-   -   the shape of the heart chamber walls, excluding the hollow        region within the chambers;    -   the arterial wall, excluding the hollow region within the        artery; or    -   the shape of the bladder, excluding the hollow region within the        bladder.        It is noted that nerve structures are potentially confined        within the tissues defined by the image masks. The hollow spaces        (potentially filled with fluid such as blood, urine or other        fluids) are expected to be nerve structure free. Optionally,        image masks include tissue surrounding the organ of interest.

The image masks are defined, for example, based on:

-   -   image segmentation—such as according to the ability of the        system to segment the image;    -   tissue type—such as muscle vs. connective tissue;    -   organ size;    -   sub-structures within the organ—such as heart chambers, liver        lobes, or kidney parts;

or another method.

Different image masks are optionally generated for different tissuetypes, and/or for GPs at different locations within the organ. Forexample, for each of the GPs within the epicardium and myocardium, arespective set of image masks is generated. Optionally, image masks aregenerated for fat pads.

The image mask comprises, for example, a 2-D surface and/or 3-D volumewith shape and/or size selected based on tissues and/or organ partswithin the anatomical image. The image mask optionally corresponds toanatomical parts believed to contain the neural tissue for imaging, suchas GPs. For example, the mask corresponds to the: walls of the fourheart chambers, intestinal wall, bladder wall, renal artery, aorticbranch region of the renal artery, kidney, and/or another structure. Inmore particular examples, the image mask is generated to contain GPswithin the epicardial and/or myocardial tissue of the heart, or kidneyinnervating GPs at the aorta-renal artery junction.

Optionally, image masks are generated based on an estimated location ofthe GPs. For example, an estimated location is based on normal patientanatomy, an initial model of the ANS for a patient, and/or knownprevious ablation or other medical data, such as indications of missingor ablated nervous tissue. Optionally, image masks are generated basedon an estimated location of the GPs and dimensions of an internal bodypart inferred, for example, from an anatomical image. Potentially, thisprovides an advantage when GPs are not visible on the anatomical image.

Optionally, generated image masks correspond to the segments of theanatomical image. For example, the heart is segmented into chamber wallsand the generated image masks correspond to the chamber walls ofinterest.

In some embodiments of the invention, at block 372, the image masks areapplied to the functional image. Alternatively or additionally, theimage masks are applied to the functional data. Alternatively oradditionally, the image masks are applied to combined functional andanatomical images and/or data, for example, overlaid images.

Optionally, the image masks are applied based on the registrationprocess (block 368). The anatomical information serves as a guide, usingthe selected image masks, for selective reconstruction of GP relateddata within the functional image. The image masks may be correlated withthe image to contain anatomical structures having the neural tissues.The application may be based on the image registration, for example,applied based on a common coordinate system. The image masks may beapplied to a certain type of tissue containing neural tissue. Forexample, the image masks may be applied to the epicardium of the heart.The image mask may be applied to have its inner surface aligned with theepicardial surface of the chamber wall, such that the image maskcontains the epicardial space encompassing the chamber.

Optionally, the generated image mask is correlated with the functionaldata for guiding the reconstruction of a functional image depicting thetarget nerve tissue.

In some embodiments of the invention, at block 374, functional activityis calculated within the applied image mask space. Optionally, theaverage functional activity is calculated. Optionally, the standarddeviation of the functional activity is calculated. For the heartexample, the functional activity is calculated around each chamberseparately, and around the entire heart. Average activity for thechambers may be denoted by A1LV, A1RV, A1LA, and A1RA. Average activityfor the heart may be denoted by A1H. Standard deviation of the activitymay be denoted by SD1LV, SD1RV, SD1LA, SD1RA, and SD1H. Optionally,average activity and/or standard deviation may be calculated for theentire functional image or data. Optionally, average activity and/orstandard deviation is pre-set, e.g., based on previous imaging of thesame patient, based on “normal” patient activity etc.

In some embodiments of the invention, at block 378, GPs are identifiedwithin the applied image mask space. It should be noted that the term“GP” is used for ease of discussion, and that the method is optionallyapplied in some embodiments for identifying ANS component(s) or forextracting or identifying other information relating to neuralactivities, or other tissues. Alternatively or additionally, GPs areidentified within the organ volume and/or nearby tissues. Optionally,GPs identified within multiple different image masks that are combinedinto a single image of all the identified GPs, for example, theidentified GPs within the organ. Alternatively or additionally, GPsidentified within corresponding image masks of multiple frames over timeare combined—such as all image masks of the LV myocardium during thecardiac cycle.

Optionally, areas of extreme activity are identified. For example,epicardial GPs (EGP) and/or myocardial GPs (MGP) are identified based onextreme mIBG activity.

Optionally, GPs are identified based on one or more predefinedthresholds and/or rules. Optionally, GPs are identified based on size.Alternatively or additionally, GPs are identified based on activitylevel in reference to average activity and/or surrounding activity.Alternatively or additionally, GPs are identified based on connectivitybetween GPs.

In some embodiments, the GP is identified as an object within aparticular size constraint. The constraint is, for example, at leastabout 4×4×4 mm, such as for an EGP; or about 2×2×2 mm, such as for anMGP. Alternatively or additionally, the GP is identified by comparingcalculated activity (image intensity) of a certain region to surroundingactivity in the same image mask. Alternatively or additionally, the GPis identified by comparing calculated activity within the image mask toactivity in another image mask. For example, the EGP is identified assatisfying the rule that the total activity of the EGP is a predefinedfactor times the standard deviation (SD1 and/or SD2), above averageactivity (A1 and/or A2), and/or the adjacent activity surrounding it islower than half of the EGP activity. Optionally, activity is correctedfor volume. Optionally, the user selects and/or modifies the predefinedfactor. For example, the MGP is identified as satisfying the rule thatthe total activity of the MGP is another predefined factor times thestandard deviation (SD1 and/or SD2), above average activity (A1 and/orA2), and/or the adjacent activity surrounding it is lower than half ofthe MGP activity, optionally corrected for volume. Optionally, the userselects and/or modifies the predefined factor.

Optionally, identification of GPs is performed per frame, optionally perframe of the dynamic cycle (e.g., cardiac cycle).

In some embodiments, the identified GP is automatically related to atissue type. Optionally, the identified GP is related to the tissue typebased on the applied image mask. Alternatively or additionally, theidentified GP is related to the tissue type based on the characteristicsof the intensity readings. For example, large sizes (denoting large GPs)are potentially only to be found in certain tissues. Optionally,different types of GPs are related to different tissues. For example,myocardial GPs are related to the myocardium and/or epicardial GPs arerelated to the epicardium.

In some embodiments of the invention, at block 380, one or moreparameters are calculated for the identified GPs (also referred toherein as GP parameters). Examples of parameters include:

-   -   average size;    -   specific activity—expressed, for example, in counts per voxel        and/or

GP/average counts in the corresponding image mask volume;

-   -   power spectra—for example, the power below 1 Hz, power between        1-5 Hz, and/or a ratio of high to low frequencies;    -   normalized power spectra;    -   GP connectivity map—for example, connectivity and interaction        between different GPs; and/or    -   number of GPs per predefined area—expressed, for example, as GP        density number/cm².

For identified EGP, one or more of following parameters is calculated insome embodiments: EGP size, EGP specific activity, EPG power spectragraph, EGP normalized power spectra, and/or a map of EGP connectivity.EGP normalized power spectra are calculated, in some embodiments, as thedifference between the EGP power at different frequencies minus thepower of the total counts from the myocardial image mask space.

Optionally, calculation of GP parameters is performed per frame,optionally per frame of the dynamic cycle (e.g., cardiac cycle).

In some embodiments of the invention, at block 382, the calculatedand/or other parameters are normalized. Normalization optionally takesplace at one or more blocks of the method, for example, during and/orafter acquiring the functional and/or anatomical images, uponcalculation of functional activity, upon identification of GPs, uponcalculating parameters for the GP, upon comparison of data over time, orat other blocks.

Examples of normalization techniques include:

-   -   raw data;    -   raw data divided by the raw data value in a known fixed        anatomical location acquired at roughly the same time, for        example, the activity of the tracer in the patient's        mediastinum;    -   normalization to a normal patient data set;    -   normalization to a value of the activity at the first or the        last image acquisition from a sequence of acquisitions;    -   normalization to value acquired in different physiological        states such as rest/stress;    -   a combination of some or all of the above; and/or    -   other methods.

Alternatively, normalization is performed instead of and/or in additionto the normalization of block 382 before a different block in theprocess. For example, normalization is optionally applied before GPs areidentified in block 378. Normalization potentially assists identifyingthe GPs. For example, activity at a local region, such as mIBG activity,is compared to an average value and/or standard deviation across theorgan volume, within the image mask space and/or relative to apredefined threshold.

Alternatively or additionally, the calculated data (e.g., blocks 374,378, 380) and/or measured functional intensity are corrected forsensitivity. Optionally, sensitivity correction is performed within eachimage mask and/or in related image masks. For example, different areaspotentially have relatively higher or lower sensitivity to uptake of theradioagent. Optionally, the anatomical data is correlated to thesensitivity. Optionally, the image masks are generated (block 370) basedon different sensitivity levels; for example: one set of image masks forhigher sensitivity nerve structures, and another set of image masks forlower sensitivity nerve structures. Optionally, the differentsensitivities are normalized to a common baseline.

Alternatively or additionally, measurements of the functional data arenormalized. For example, measurements of uptake of the radioagent arenormalized to the level of corresponding chemical in the patient.Optionally, intensity measurements are normalized according to the levelof activity of GP being identified. Optionally, measurements denotingactivity of the GPs are taken. For example, in the case of mIBG,measurements are optionally normalized to the level of norepinephrine(NE), adrenaline and/or epinephrine in the patient. Optionally, thelevel of NE is measured in the blood, urine, or other body fluids.Intensity of mIBG uptake is normalized based on the measured NE.

Additionally or alternatively, mIBG measurements are normalized to adecay function, such as decay over time since injection of mIBG. Inanother example, the level of activity is measured by non-chemicalmethods. For example, normalization of mIBG is performed based onmeasurements taken during a cardiac stress test. Measurements comprise,for example, ECG measurements, heart rate, cardiac output, and/or othermeasurements. Optionally, measurements are correlated with levels ofactivity of the GPs being identified, for example by a table,mathematical equation, or other method.

Additionally or alternatively, measurements of functional data arenormalized to a level of one or more electrical properties. For example,functional data are normalized to impulse conduction velocity,refractory period, a measured electrical potential (at one or morephases of contractile state), or another property of the electricalactivity of the tissue. Optionally, additional weight is given toregions where conduction is particularly poor: slow to transmit and/orslow to recover, for instance. This is a potential advantage, forexample, when evaluating a heart region for severity of disease, and/orfor comparing regions for their relative severity of disease.

In some embodiments of the invention, at block 384, data is comparedover time. Optionally, changes in GP parameters over time areidentified. Optionally, dynamic changes of the calculated parametersbetween different acquisition times are determined. For example, thechanges in GP activity over time are calculated, from injection till 6hours post injection, by repeating the image acquisition several timesduring this time window. The functional images are optionally acquiredat more than one time after the tracer injection.

In some embodiments of the invention, at block 386, a functional imageis reconstructed based on the mask applied to the functional data and/orimage. Alternatively or additionally, an image is reconstructed based onthe mask applied to the combined functional and anatomical data and/orimages. The reconstructed image potentially contains the identified GPs,for example, as regions of increased intensity. The reconstructed imageis optionally overlaid on the anatomical image, illustrating thephysical location of the GPs.

Alternatively or additionally, the characteristics of the GPs within thefunctional image are reconstructed. The reconstruction is instructed bythe image mask.

In some embodiments of the invention, at block 388, the calculatedresults from, for example, block 378, 380, 382 and/or 384, and/orreconstructed images (block 386) are provided for presentation orotherwise provided to the operator. They are, for example, presented ona monitor to a physician. Additionally or alternatively, the calculatedresults and/or reconstructed images are stored in a memory for futureuse, such as diagnosis. The calculated results potentially assist indiagnosing the patient and/or in guiding treatment.

Optionally, the results are provided for presentation on a certainframe, for example, the end systolic frame. Alternatively, results areprovided for presentation on multiple frames, for example, a video ofthe cardiac cycle.

In some embodiments, the reconstructed functional image or combinedfunctional and anatomical image is provided for registration during atreatment procedure. Optionally, the reconstructed functional image isoverlaid on and/or registered with anatomical images obtained during thetreatment procedure. Overlaid and/or registered images are optionallyused by the operator to physically determine locations of the GPs duringthe treatment.

The method of FIG. 3B has been described with reference to the heart.The method is not limited to the heart, and is used in some embodimentsfor other organs, including hollow fluid filled organs such as stomach,aorta, or bladder; and/or solid organs such as kidney or liver. GPsand/or nerve endings are identifiable in these other organs in someembodiments. For example, the aorta is segmented based on surroundingstructure such as bones, muscles, and/or branching arteries; and imagemasks generated accordingly. The liver, in an exemplary embodiment, issegmented based on anatomical liver lobe divisions.

FIG. 4 is a flowchart 400 of a method of finding cardiac zones withreduced control, in accordance with some exemplary embodiments of theinvention. As noted above, tissue which has fewer types of control thanother tissue is expected to react differently (e.g., mechanically and/orelectrically) to changes in cardiac conditions and/or timing of suchchanges.

At 402 tissue is measured under a first set of conditions, for example,low stress. All tissue (or at least neighboring tissue) may act the sameway, for example, exhibiting same conduction velocities, refractoryperiods, plateau durations and/or other action potential properties.Optionally, the measurement uses an EP catheter system, such as theBiosense-Webster Carto® system.

At 404 the measurement conditions are changed (at least once) andmeasurement repeated. For example, a greater preload may be applied toheart. Optionally or alternatively, a stress causing agent or exercisemay be applied. Optionally or alternatively, a hormone such asadrenaline may be applied. It should be noted that the differentconditions may be acute or may be more steady. One example in a changein condition is a sudden recruitment of cardiac output to deal with astress condition. Another example is after a few seconds or minutes whenhormonal levels increase and when, possibly, the stress is reduced sothat the nervous system acts to reduce excitability of muscle cells (butinsufficiently in muscle segments with reduced nervous control).

At 406 areas with changed behavior are detected. Optionally, only areasnear infarct scars are measured, as such areas may be more likely tohave the combination of viability and reduced control. Examples ofexpected changes are changes in EP parameters such as shape of actionpotential and conduction velocity and changes in mechanical activity,such as contraction strength and/or speed.

While measurement may be using a catheter, in some embodiments,measurement uses radioimaging, for example, single isotope imaging, suchas imaging using viability-indicating tracers and/or imaging usingnervous control-indicating tracers. Optionally, both imaging andmeasurement under different conditions are used (e.g., acquiringone-tracer or two-tracer images under various conditions).

At block 408, a map showing the various areas (portions) detected isconstructed. Construction is, for example, according to operationsdescribed in relation to FIG. 5.

FIG. 5 is a flowchart 500 of a method of reducing cardiac arrhythmiaand/or assessing risk and/or diagnosing and/or therapy planning, inaccordance with some exemplary embodiments of the invention.

At block 502, a map showing zones with reduced nervous control and/orreduced viability is provided, for example, using methods describedherein.

At 504 problematic regions are optionally identified. For example, zonesthat have a certain size and/or location and combine tissue viabilityand reduced nervous control, may be identified. In one example, thelocation is the location of an SA (sinus) node (or other location whichacts as a source of the cardiac cycle in a particular patient). Reducednervous control of the SA node may cause rhythm disturbances, forexample, by causing the pacing origin to migrate under differentconditions of nervous and/or hormonal activity.

If the provided image is a 4-D image, regions that move over time (e.g.,for which amount of control varies with physiological condition) may beidentified.

In another example, hibernating or ischemic regions are identified asproblematic.

In another example, a tracer with antibodies or other affinity for ahormonal receptor (for example, of a type known in the art) is used toidentify regions where hormonal control is unbalanced with other typesof control and/or functionality.

Various analyses may be applied to such identified regions. In someembodiments, for example, at 506, the timing of contraction of differentparts of the heart may be determined, for example, to assess changes inconduction patterns which increase (or decrease) cardiac output and/orchange a risk of aneurysm.

In some embodiments, for example at 508, mechanical behavior of theheart may be analyzed. For example, regions with reduced nervous controlmay under-contract at some times, over-contract at other times and/ormay be ballooned by increased pressure in the heart.

In some embodiments, for example, at 510, conduction pathways may beanalyzed. Such analysis can include, for example, an estimation of AFrisk (e.g., based on size, shape and/or pattern of reduced control zonesand/or reduced viability zones in an atrium). In another example, anestimation of ventricular arrhythmia (e.g., VT) risk is provided, forexample, by identifying long conduction pathways (e.g., along reducedcontrol zones). Such analysis may also take into account EP data, forexample, which indicates areas with ischemia and/or areas with reducedconduction velocity and/or areas with suspected (e.g., based on ECG)contribution to arrhythmia, such as by acting as foci or as reentrycircuits (reentrant loop).

At 512 treatment is planned. The planned treatment, in some embodiments,is for addressing a risk assessed in one of blocks 506-510. Optionally,the treatment is for another purpose. For example, identification ofreduced control regions can be used to select an optimal place for apacemaker lead.

In some embodiments, the analysis of the image is used to interpret EPmeasurements and/or mechanical measurements (e.g., contraction amount,speed, force and/or change in thickness). For example, a low signal mayhave different meanings if acquired at a low control region (e.g., anymay need to be corrected based on the patient's physiological condition,such as hormonal levels. In addition, the identification of a lowcontrol zone can assist in interpreting electrical measurements whichare associated with weaker than expected mechanical activity.

In some embodiments, low control zones are used to assess the usefulnessand/or desirability of inserting a stent or performing PCTA or othervessel modification. For example, increasing blood flow to a problematicregion may increase the chance of an arrhythmia.

In some embodiments, low control zones are used to assess the usefulnessof gene therapy or other treatment designed to convert fiber tissue tonon-fiber tissue or healing weak tissue (which generally cannot be donefor fiber tissue). For example, increasing the amount of uncontrolledtissue in the heart may be undesirable. Conversely, creating acontiguous region of uncontrolled tissue may be desirable in somehearts, and undesirable in others. In another example, rehabilitatingtissue may be more desirable if the control infrastructure is availableat or near that tissue to be rehabilitated.

In some embodiments, low control zones are used to diagnose a mechanicalcondition such as HOCM or various cardiomyopathies, such as dilatedcardiomyopathies. For example, HOCM may manifest due to uncontrolledtissue failing to contract fast enough and/or soon enough duringexercise.

In some embodiments, low control zones are used to assess a risk ofcardiac dysfunction due to ischemia or a further infarct and/or assess aprognosis for a patient with heart failure.

It is noted that identification of low control zones, optionallytogether with information such as viability of tissue, electricalbehavior and/or blood flow may be used to diagnose conditions otherwisediagnosed only using biopsy, sometimes after death.

At 514, the heart is optionally treated, for example, by ablation, byvascular manipulation (e.g., stent implantation), heart reshapingapparatus implantation, valve implantation, electrical stimulation,surgery and/or pharmaceuticals.

It is noted that in some cases there is no need to actually detectregions with reduced control. Rather, for example, using the insightsdescribed herein, a doctor can diagnose a patient based on symptoms aslikely suffering from a condition associated with low control regions(e.g., arrhythmia after exercise and/or at a delay after providinghormonal injection). Optionally, ablation may then be applied near knownor identified dead zones in the heart. Optionally, the ablationlocations are selected to ensure that conduction pathways through lowcontrol tissue, are short enough and/or located at a safe location withrespect to other tissue, other dead zones and/or timing of activation inthe cardiac cycle.

In an exemplary embodiment of the invention, treatment includes pacing.For example, pacing, such as anti-arrhythmia pacing, may be applied ator near a low control zone, for example, such that the pacing obviatesthe need for control to avoid arrhythmia or provides arrhythmia controlat a location in need thereof. Optionally, pacing is set according to anunderstanding of the underlying pathology. For example, tissue near apotential re-entrant stimulation loop is paced so that refractoryproperties of the tissue allow the loop to be blocked fromself-propagation. Optionally, pacing is changed in response toconditions likely to lead to an arrhythmia. For example, an increase inheart rate is considered differently, according to how recently and/orhow quickly the increase occurred (under neural vs. hormonal control,for example). Optionally, the logic which manages the pacing iscontained within a pacemaker, for example, an implanted pacemakerdevice.

Electrode location may also be an issue for defibrillation, especiallydefibrillation methods that first attempt to stop fibrillation bycapture. Uncontrolled tissue may be easier or more difficult to capture,depending, for example, on the patient, and this may drive electrodeplacement and/or sensing location. In an exemplary embodiment of theinvention, a device for electrical therapy includes a sensor (e.g.,and/or is suitable implanted and/or programmed) which is intentionallyplaced in controlled regions (e.g., to assess a correct activationprofile of the heart) and/or in non-controlled regions (e.g., to assessactivation of uncontrolled portions of the heart which may have adifferent refractory period). Optionally, sensing is provided both atcontrolled and at uncontrolled regions. Optionally, when detecting alarge enough divergence between the activities at the two regions, adetermination that an arrhythmia is imminent or ongoing is generated.

In another example, pharmaceutical therapy may be selected so as tocompensate for the existence of uncontrolled tissue. For example, betablockers which initially increase tissue sensitivity to hormones andthen reduce such sensitivity may be more or less desirable in somepatients, for example, based on the pattern, size and/or location oflow-control viable regions therein.

In another example, anti-arrhythmia drugs which affect a refractoryperiod may be prescribed based on the detection of low control areaswhich cause and/or sustain arrhythmia due to a (relatively) shortedrefractory period thereof.

In an example of negative treatment, treatment to revive hibernating orischemic tissue may be avoided if it may increase problem areas.

FIG. 6 is a schematic showing a system 600 for identifying tissue zoneswith reduced nervous control in a heart 602, in accordance with someexemplary embodiments of the invention.

An imager 604, for example a D-SPECT device as described above is usedto acquire information about the heart. Optionally, the imager alsoacquires a structural image or images to provide a model for thereconstructions. Optionally or alternatively, imager 604 also collectscardiac phase information and/or respiratory phase information. It isnoted that such information may also be reconstructed from the acquireddata, in some embodiments of the invention.

An image reconstructor 606, optionally bundled with imager 604, butalternatively provided at a remote location, may be used to reconstructthe reduced-control-showing image, for example, as described above.

An image analyzer 608 optionally bundled with one or both of imager 604and image reconstructor 606 is optionally provided and used to performautomatic and/or semi-automatic analysis of the image, for example, toidentify potential arrhythmia sources.

Optionally, a workstation 610 is used to control one or more of imager604, reconstructor 606 and analyzer 608 and/or to display resultsgenerated thereby.

In an exemplary embodiment of the invention, a navigational system 612is provided which is optionally controlled by work station 610 and whichmay be loaded with targeting and/or map information provided by theimage. In one example, the navigational system 612 comprises a catheterwith a position sensor (e.g., the Biosense-Webster Carto® system) andthe image is used to guide a procedure performed using the catheter.Such a navigation system 612 may be used with other cath lab equipmentsuch as an X-ray machine. Viability and/or nervous control indicationsand/or indications of tissue being problematic are optionally overlaidon an image acquired by the X-ray machine. Optionally, registration isprovided manually or using the above mentioned position sensor.

In an exemplary embodiment of the invention, the map is used for safety,for example, to indicate to a user that he is about to ablate a viableand well-controlled region, when a nearby region is not well-controlledand may be a better target. Optionally or alternatively, when providingtemporary pacing, the system can indicate that pacing is being providedat a location where lack of nervous control interferes with a desiredresult (or perhaps enhances it).

FIG. 7 is a set 700 of nuclear medicine images showing tissue zones withreduced nervous control, in accordance with some exemplary embodimentsof the invention. Shown are three images of a left atrium 702. The leftimage shows a radioimage reconstructed using a MIBI tracer (e.g.,Sestamibi) which indicates viability. Red areas 704 indicate completescarring/fibrosis and yellow areas 706 (mainly at the border lines inthis example) indicate partial fibrosis. In other cases, partialfibrosis has been identified (e.g., using methods of some embodiments ofthe present invention) in the middle of a supposedly ablated (orotherwise damaged) region. At the top of the image the lack ofcontiguity of the ablated areas can be seen.

The middle image shows a radioimage reconstructed using a tracer takenup by nerve endings (e.g., mIBG). Reference 710 indicates areas withsignificantly reduced innervation.

The left figure shows what is already visually apparent, which is thevery large mismatch between scarring and denervation. Specifically, anarea 712 of innervation and less viable tissue is shown, as is an area714 of denervated but viable tissue.

FIG. 8 is a set 800 of nuclear medicine images showing tissue zones withreduced nervous control, in accordance with some exemplary embodimentsof the invention. Shown are three images of a left ventricle 802.

The left image shows a radioimage reconstructed using a MIBI tracer(e.g., Sestamibi) which indicates viability. Red areas 804 indicatecomplete scarring/fibrosis and yellow areas 806 (mainly at the borderlines in this example) indicate partial fibrosis.

The middle image shows a radioimage reconstructed using a tracer takenup by nerve endings (e.g., mIBG). Reference 810 indicates areas withsignificantly reduced innervation.

The left figure shows what is already visually apparent, which is thevery large mismatch between scarring and denervation. Specifically, anarea 812 of innervation and less viable tissue is shown, as is an area814 of denervated but viable tissue. It is noted that the patientsuffers from ventricular arrhythmia, caused, it is hypothesized, by thelarge size and/or boundary of area 814 and/or a gap 816 between the twoareas.

It should be noted that the method of normalization and display used inFIGS. 8-9 emphasizes health/innervation mismatches in particular.Regions of notionally equivalent health and innervation are shown ingreen in the right-most images whether effectively healthy, or not.

Reference is now made to FIGS. 9 and 11-13, which are sets 900, 1100,1200, 1300 of nuclear medicine images showing left atrium tissue zoneswith scarring and/or abnormal nervous control, according to someexemplary embodiments of the invention. Reference is also made to FIG.10, which is a set 1000, of nuclear medicine images showing leftventricle tissue zones with scarring and/or abnormal nervous control,according to some exemplary embodiments of the invention.

The left images 903, 1003, 1103, 1203 and 1303 each show a radioimagereconstructed using a MIBI tracer (e.g., Sestamibi) which indicatesviability. Red (darker) areas 904, 1004, 1104, 1204 and 1304 indicatecomplete scarring/fibrosis and yellow areas 905, 1005, 1105, 1205 and1305 indicate partial fibrosis.

The middle images 906, 1006, 1106, 1206 and 1306 each show a radioimagereconstructed using a tracer taken up by nerve endings (e.g., mIBG). Red(darker) areas 907, 1007, 1107, 1207 and 1307 indicate areas withsignificantly reduced innervation. Yellow/black (hatched) areas 908,1008, 1108, 1208 and 1308 indicate areas of hyperactive innervation.Hyperactive innervation potentially occurs, for example, if neuraltissue acquires a loss of feedback control on growth, maintenance,and/or activity. For example, loss of trophic support due to death ofone tissue region potentially encourages excess regrowth in another.Additionally or alternatively, loss of signaling of the effectiveness ofinnervating activity potentially results from actual tissue death,and/or acquisition of insensitivity by a portion of denervated tissue.In such a case, excess signaling potentially represents a nervous systemattempting to counteract the wrong problem.

The right images 909, 1009, 1109, 1209 and 1309 each show what isalready visually apparent, which is the very large mismatch betweenscarring and denervation. In FIGS. 9-13, normalization and display ofresults is such that four different categories of region are shown: bothtypes of mismatch (greater innervation or greater tissue viability), andmatched-healthy, and matched-unhealthy. Specifically, blue (darkestsolid) areas 910, 1010, 1110, 1210 and 1310 indicate innervated but lessviable tissue; yellow/black (hatched) areas 911, 1011, 1111, 1211 and1311 indicate denervated but viable tissue; and red (solid, intermediatedarkness) areas 912, 1012, 1112, 1212 and 1312 indicate non-innervated,non-viable tissue.

In some cases, innervated but less viable tissue areas 910, 1010, 1110,1210 and 1310 comprise scarring which is non-transmural; that is,scarring which does not extend entirely across the thickness of thetissue. Before loss of innervation, ANS activity is potentially found onboth sides of the heart wall. Optionally, loss of innervation signalfrom just one side of the wall is considered to be associated withpartial scarring, while loss of innervation (and thus of activitysignal) on both sides is associated with complete (transmural) scarring.The bulk of inner and outer innervation is either de-excitatory orexcitatory for the heart (for example, respectively), which providesanother potential method of estimating where damage has occurred to theheart based on properties of the ANS innervation which remains intact.

Remediation of an innervation/vitality imbalance such as is shown inexamples of FIGS. 9-13 optionally comprises one or more of thestrategies for ablation and/or stimulation described hereinabove. Asexamples:

-   -   a tissue region which has escaped neural control is ablated;    -   function of a tissue region which has escaped neural control is        brought under the control of direct or indirect artificial        stimulation, and/or undergoes restoration of innervation, for        example by application of trophic factors encouraging regrowth,        and/or nerve branch transplantation;    -   function of a tissue region which has escaped neural control is        weakened or paralyzed—for example, stunned and/or dosed with        function-blocking drug;    -   stimulation of a tissue region which is innervated but        under-stimulated is enhanced;    -   a tissue region which remains under neural control, but        potentially contributes to organ function instabilities thereby,        is denervated, and/or brought under control of artificial        stimulation;    -   a tissue region which remains under neural control, but        potentially contributes to organ function instabilities thereby,        is weakened, ablated, and/or paralyzed.    -   a tissue region which remains under neural control, but is        insufficiently responsive, is directly or indirectly        overstimulated—for example, by electrode stimulation of the        region or its innervation, by transplantation of a nerve branch        from another organ region, and/or by dosing with a        sensitivity-increasing drug.

In some embodiments of the invention, where ablation is to be performed,a map showing the relative distributions of tissue vitality and tissueinnervation is used in illustrating the potential effects of theablation. For example, a planned ablation is added to a model of theheart tissue. In some embodiments, effects on excitability produced bythe planned ablation are modeled. Optionally, modeling is of a range ofconditions, for example, of modulated velocities of transmission. Insome embodiments, where a potential condition leading to a recurrenttransmission characteristic of arrhythmia is detected, an alert to thiseffect is provided. In some embodiments, modification of the proposedablation is proposed by the system, based, for example, on iterativechanges with remodeling of effects on performance under differentoperating conditions.

Reference is now made to FIGS. 14A-14D, which illustrate a disease modeof a heart 1400, for which activity imaging provides an understandingwhich guides a well-localized application of treatment, according tosome exemplary embodiments of the invention.

Under a regime of healthy functioning, a heart 1400 contracts accordingto signaling which propagates across its surface in a relatively orderlywave impulse, as indicated, for example, by arrows 1401 (FIG. 14A). Inan exemplary instance of heart damage (FIG. 14B), portion of the impulse1402, 1405 are disturbed as it passes through a patchwork of denervated(optionally transmural) scarring (red or medium-dark gray), innervated(optionally, non-transmural) scarring (blue or dark gray), healthy(green or light-gray), and denervated but viable (orange-striped orlight-gray striped) tissue. Portions of the signaling impulse 1401remain within healthy tissue, and, accordingly, propagate quickly todistal portions of the heart. Other portions of the impulse soon reachthe boundary of a vital but denervated area. When passing into viable,denervated tissue, the impulse 1403 is potentially slowed, for exampledue to alteration of electrical propagation properties related to thedenervation. In normal heart tissue, innervation, together with hormonalinfluences, acts as a control on conduction velocity (setting theoverall pace of heart contractions). However, in denervated tissue, thedirect innervating component is lost, typically resulting in a lowerbasal level of impulse conduction velocity.

At a boundary with non-viable, non-innervated scar tissue, impulsepropagation is potentially blocked entirely.

A situation which can potentially arise in such a condition is that aregion of tissue is positioned to receive propagation signals from twodifferent directions. For example, in FIG. 14B, a portion of the impulse1404 proceeds in a retrograde direction from a point which, for example,is just beyond a denervated and scarred region, but adjacent to a regionwhich receives stimulation from an uninterruptedly fast impulse. Thismode of operation potentially results in a poorly coordinatedcontraction, but not necessarily in arrhythmia. However, in someinstances, such a condition has a second mode of operation available toit.

In FIG. 14C, such a mode is shown. Here, as before, a rapidly arrivingimpulse propagates from region 1410, converting, when crossing to adenervated but viable region, to a slow impulse 1412. However, undersome timing conditions, the slow wave continues across the whole of thedenervated but viable heart section, to reach a fast-propagating regionagain, and continue as a fast-propagating impulse 1414.

A difference in timing conditions which can prevent the limiting of thepropagation of such an impulse comprises, for example, a sufficientslowing of impulse 1412, such that it reaches the region of impulse 1414after this region has recovered from its most recent refractory periodfollowing contraction. In another example, two normal impulses occur tooclose together in time (relative to the tissue refractory period), suchthat the first arrival of the second impulse is blocked bystill-refractory tissue. However, the retrograde portion of the secondimpulse potentially reaches the block region after the refractoryperiod. In either case, or in another configuration, modulation ofpropagation by ANS tonus potentially is involved in changing theunderlying propagation properties of the heart tissue, such thatretrograde propagation changes its extent.

In some instances, this pattern of retrograde activation becomesself-reinforcing. For example, the retrograde impulse may reachfast-transmitting tissue again, at a time past its last refractoryperiod. Then the impulse again turns anterograde, and, potentially, theimpulse enters a self-stimulating loop. Potentially, this loop resistsbeing broken by normal impulses, by maintaining tissue in a state whichis almost always refractory, except for a few moments before the nextcircular impulse hits it, and/or by creating a back-propagating “wall”of refractory tissue. Thus, the heart potentially enters into a periodof cardiac arrhythmia.

In terms of tissue vitality and ANS functional mapping, the hallmarks ofone type of potentially arrhythmia-prone configuration have beendescribed: adjacent regions of fast and slow impulse propagation(innervated and denervated), separated by a region inert to impulsepropagation. It can be readily understood from this example that otherself-reinforcing configurations potentially arise wherever a disturbanceto the organization of timing and function has occurred. A particulardanger of a fully blocking zone is that it creates a break in thecontinuity of local propagation, such that adjacent tissue is no longerguaranteed to have a substantially identical refractory period, or evena time of initial activation. In some cases, the fully blocking zone isa normal part of the anatomy (such as a valve ring), the conversion to afibrillation trigger arising from some other local disruption ofvitality and/or innervation.

FIG. 14D, in some embodiments, shows how analysis of the ANS functionalmapping potentially serves to suggest a treatment which prevents theheart from entering the loop mode of FIG. 14C. An ablation 1420 is madeat a region which bisects the pattern of loop activation. Optionally,ablation 1420 is placed at a location which extends an already existingtransmural scar to become so long that self-reinforcing propagation canno longer occur. Optionally, an ablation is made to a potentiallyarrhythmia-generating region which does not comprise a transmural scaralready. The potential of a transmural scar region to serve as the focusof an arrhythmia center is in part dependent on its interaction with thetiming of impulses that move past it. In some embodiments, asufficiently long ablation comprises a treatment to prevent a regionfrom generating an arrhythmia, whether or not the region initiallycomprises a transmural scar. Potentially, the length is determined bythe length necessary to prevent retrograde propagation from setting up aresonant cycle.

Reference is now made to FIG. 15, which is a block diagram of a modelANS modeling system/unit 1606, in accordance with some exemplaryembodiments of the invention.

In some embodiments, ANS modeling system/unit 1606 is provided as a partof a system 1500 including functionalities with which ANS modelingsystem/unit coordinates in series or in parallel. For example, a system1500 includes a functional imaging modality 1608A (such as a SPECTimager), and/or an anatomical modeling modality 1608B. Anatomical imagemodality data comprises data obtained, for example, from a CT (X-ray orgamma-ray, for instance), MRI, 3-D ultrasound, 2-D ultrasound,fluoroscopy, or by another modality. Optionally, an ANS modelingsystem/unit is comprised within another system configuration, such as asystem 1600, as described in relation to FIG. 16 hereinbelow.

In some embodiments of the invention, ANS module 1606 receivesfunctional images and/or imaging data 1612A (for example, as produced byfunctional imaging modality 1608A); and anatomical images and/or imagingdata 1612B (for example, as produced by anatomical imaging modality1608B).

The ANS module itself produces model information 1620 comprisinginformation, about, for example, GP locations, interconnections and/oractivity levels. In some embodiments, image data within GP locationsresolves one or more distinct and/or identifiable GP regions. Productionof an ANS model comprises, for example, one or more of the blocksdescribed in relation to FIG. 3B, hereinabove.

In some embodiments of the invention, ANS module 1606 comprisesprocessor controller 1506. Processor/controller carries outcomputational tasks of ANS model generation, for example, computationaltasks described in relation to FIG. 3B, hereinabove. Optionally, ANSmodule 1606 is provided with a GUI 1508. In some embodiments, ANS module1606 comprises memory 1504, used, for example to receive and storeimages, associated data, model information, and/or process/controllerinstructions. Optionally, GUI 1508 is used, for example, in theselection of image sources, images, and/or regions of data for analysis.Optionally or alternatively, GUI 1508 is used, for example, to showmodel results; for example: regions of tissue health or disease, regionsof innervation or lack of innervation, regions of nervous systemactivity/inactivity, and/or any of these regions in relation to oneanother. In some embodiments, ANS module 1606 comprises a workstation1510. The workstation itself, in some embodiments, optionally comprisesthe processor/controller 1506 and/or GUI 1508. In some embodiments,functions of workstation 1510 are distributed; for example, at least apart of ANS modeling carried out by processor/controller 1506 iscalculated remotely, for example, as a provided service.

In some embodiments, a system 1500 includes one or more tools for atreatment option such as GP ablation, stimulation, anesthesia, oranother neuromodulatory intervention. In some embodiments, system 1500is operable for guidance of a probe for treatment based on real-timedisplay of a probe and ANS map in registration, direct (for example,robotic) guidance of probe position, or another method of ANSmap-guidedtreatment and/or treatment probe placement.

Exemplary Diagnosis and Treatment Sub-System

Reference is now made to FIG. 16, which is a block diagram of a modelanalysis and treatment planning system/unit 1600, in accordance withsome exemplary embodiments of the invention.

In some embodiments, once a model is available, it is used for diagnosisand/or planning a treatment for example as described hereinabove. Groupsof elements comprising a system/unit 1600 include, for example, blockswithin the boundaries delineating system configurations 1600A, 1600B,1600C, 1600D, and/or another system configuration comprising blocks ofFIG. 16.

In some embodiments, unit 1600 carries out functions of various modelanalyses described herein, for example, in relation to FIG. 15. Forexample, it includes analysis/modeling subsystem 1606, as inconfiguration 1600C. In some embodiments, unit 1600 is integral toand/or co-located with imaging and/or treatment systems (for example, itincludes imaging subsystem(s) 1608, as in configuration 1600D). In someembodiments (for example, including analysis/modeling subsystem 1606),images and imaging data 1612 are received by the system/unit 1600. Insome embodiments (for example, including imaging subsystem(s) 1608),images and imaging data 1612 are generated by the system/unit 1600. Insome embodiments, imaging subsystems 1608 include an imaging modalitydescribed in relation to FIG. 15, for example, a functioning imagingmodality 1608A, and/or an anatomical imaging modality 1608B.

In some embodiments, unit 1600 (for example, configurations 1600A and/or1600B) is remotely located relative to other subsystems, and/or isdistributed. Optionally, the functions of, for example, subsystem 1600Aare provided as a service. In exemplary embodiments of the invention,rather than provide a user with a model of the ANS 1620, what isprovided is a combination model and treatment plan (for example, acombination comprising the information of model information 1620 andtreatment plan 1632) or possibly just a treatment plan 1632. Someexemplary treatment plans 1632 are described below.

In a first stage of operation of some embodiments of the invention,model information 1620 and patient information 1622 provided to adiagnosis sub-system 1602. Model information 1620 includes, for example,GP locations, interconnection and/or activity level. Patient information1622 includes, for example, patient demographics, history and/orprevious response to therapy. Optionally, diagnosis sub-system 1602 usesa diagnosis database 1624 to assist in providing a diagnosis. Diagnosisdatabase 1624 includes, for example, rules, example diagnoses, and/ormachine learning data. Optionally or alternatively, diagnosis sub-system1602 includes one or more modules which apply processing on the model toextract diagnose. In some exemplary embodiments of the invention, thediagnosis database 1624 is updatable and/or parts thereof are availableat different and/or additional cost.

The output of diagnosis system 1602, in some embodiments, is apersonalized diagnosis 1630. In some exemplary embodiments of theinvention, the diagnosis database 1624 includes a plurality oftemplates, each one optionally associated with one or more possiblediagnoses and/or including instruction for missing data to assist indiagnosis. Optionally or alternatively, at least one dynamic template isused. Such a template is potentially useful, for example, if a diseaseis characterized by a temporal pattern of behavior. Such a templateincludes, for example, multiple snapshots with a time indicator, and/ordefines a function of change over time and/or in response to a trigger.

In some exemplary embodiments of the invention, personalized diagnosis1630 is provided to a planning sub-system 1604. In some embodiments,planning sub-system 1604 generates a treatment plan suitable for thepatient, based on the diagnosis and/or best practices. Optionally, atreatment database 1626 is used to aid in treatment planning. Thetreatment database 1626 includes, for example, exemplary treatments,and/or rules for applying them.

Optionally or alternatively, planning sub-system 1604 uses modules toplan various parts of the treatment and/or to determine if parts of thetreatment are reasonable and/or safe. Optionally, model information 1620and/or patient information 1622 also serve as input for the treatmentplanning. For example, the information 1620, 1622 is used to helpdetermine what effect a treatment may have on a patient. In someembodiments, the result is a treatment plan 1632.

In some exemplary embodiments of the invention, treatment plan 1632includes one or more of: a plurality of locations to be treated, anexpected measurement for the effect of treatment of a location,treatment parameters for one or more of the location treatments and/oralternatives for one or more of the locations. Optionally, the plan 1632includes a time line indicating the order of treatment and/or delaytimes between treatment locations.

In some exemplary embodiments of the invention, a treatment is definedwith a time scale of several minutes, hours or days; for example,defining a wait of between 1 and 1010 minutes or between 1 and 20 hoursbetween treatment locations. Waiting allows, for example, the planningof a gradual series of ablations, with observation during the intervalsbetween ablations used to evaluate progress, side-effects, and/or tomake planning adjustments according to results achieved.

It should be noted that diagnosis and/or modeling is potentiallyimproved, in some embodiments, by taking into account the effect oftreatment. In some exemplary embodiments of the invention, a treatmentplan 1632 includes a suggestion to recalculate model and/or diagnosisand/or treatment plan, for example, in response to a measurementexceeding a certain threshold or matching a certain pattern, and/orotherwise to fulfill a rule.

It is expected that during the life of a patent maturing from thisapplication many relevant radioimaging techniques will be developed andthe scope of the term radioimaging is intended to include all such newtechnologies a priori.

As used herein, the term “about” refers to within ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean: “including but not limited to”.

The term “consisting of” means: “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

The words “example” and “exemplary” are used herein to mean “serving asan example, instance or illustration”. Any embodiment described as an“example or “exemplary” is not necessarily to be construed as preferredor advantageous over other embodiments and/or to exclude theincorporation of features from other embodiments.

The word “optionally” is used herein to mean “is provided in someembodiments and not provided in other embodiments”. Any particularembodiment of the invention may include a plurality of “optional”features except insofar as such features conflict.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

What is claimed is:
 1. Apparatus comprising circuitry configured tocompare portions of a viability image comprising indications of tissuevitality for non-neural tissue within an organ of a patient withportions of a nervous control image comprising indications of autonomicinnervation of the non-neural tissue; and to generate a map indicatingportions of the non-neural tissue with viability and reduced autonomicnervous control, based on the comparison.
 2. The apparatus of claim 1,wherein the circuitry is configured to identify level of viability ofthe non-neural tissue in a region based on locations of a tracerselectively taken up by viable tissue of the non-neural tissue.
 3. Theapparatus of claim 1, wherein the circuitry is configured to identifylevel of nervous control of the non-neural tissue based on locations ofa tracer selectively taken up by nerve endings or tissue which collectsadrenaline.
 4. The apparatus of claim 1, wherein the viability image andthe nervous control image are 4-D images.
 5. The apparatus of claim 1,wherein the autonomic nervous control of the portions of the organ withvital non-neural tissue and reduced autonomic nervous control is reducedrelative to a normal level of autonomic nervous control.
 6. Theapparatus of claim 5, wherein the normal level of autonomic nervouscontrol is provided by at least one of the group consisting of: a map ofnormal autonomic nervous control activity ranges allowed for imagedportions of the organ, and one or more thresholds of autonomic nervouscontrol activity for different parts of the organ; indicating one ormore parameter ranges of normal autonomic nervous control.
 7. Theapparatus of claim 1, wherein the portions of the organ with vitalnon-neural tissue and reduced autonomic nervous control are reduced inactive autonomic innervation relative to a bordering region having anormal level of active autonomic innervation.
 8. The apparatus of claim1, wherein the autonomic innervation comprises innervation by one ormore ganglia.
 9. The apparatus of claim 1, wherein the viability imageand the nervous control image are obtained using dual isotoperadioimaging, with a first of the dual isotopes used to identifymetabolic activity in the non-neural tissue, and a second of the dualisotopes used to identify autonomic innervation of the non-neural tissuebased on at least one of the group consisting of activity of presynapticneurons, the density of receptors for neurotransmitters, and the numberof nerve endings.
 10. The apparatus of claim 1, wherein the organ whichreceives autonomic innervation comprises the heart of the patient. 11.The apparatus of claim 1, wherein the organ which receives autonomicinnervation comprises one of the group consisting of: a liver, a kidney,and an organ of the gastrointestinal tract.
 12. A system for treatingdysfunction of an organ, comprising: a modeling unit, comprisingcircuitry configured to receive functional image data of said organ anddetermine therefrom a model identifying: regions of viability ofnon-neural tissue of the organ, and regions of reduced autonomicinnervation of the non-neural tissue of the organ; a treatment planningunit, comprising circuitry configured to: match said model with adisease-treatment template, according to a disease condition modeled insaid template, and provide a treatment plan associated with saidtemplate, according to said match.
 13. The system of claim 12, whereinsaid treatment plan comprises an indication selecting a portion of bodytissue for ablation.
 14. The system according to claim 13, wherein saidorgan is a heart, and said dysfunction is arrhythmia.
 15. The systemaccording to claim 14, wherein said body tissue comprises cardiactissue.
 16. The system according to claim 15, wherein said non-neuraltissue comprises the cardiac tissue within a viable region of the organreceiving reduced-innervation.
 17. The system according to claim 14,wherein said body tissue comprises non-cardiac tissue.
 18. The systemaccording to claim 14, wherein said body tissue comprises neural tissue.19. The system according to claim 14, wherein said modeled diseasecondition comprises an indication of potential arrhythmia.
 20. Thesystem according to claim 12, wherein said organ is an organ of thegastrointestinal tract.
 21. The system according to claim 20, whereinsaid organ is the stomach.